🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal Recessive HP:0000007

Autosomal recessive inheritance

Show evidence (3 references)

CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z SUPPORT Other

ClinGen records autosomal recessive inheritance.

PMID:29058690 SUPPORT Human Clinical

"Mutation segregation was consis- tent with recessive inheritance when parental DNA was available"

Segregation in the founding families.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic"

GeneReviews recurrence risk for autosomal recessive genetic SRNS, which applies to AVIL.

?

Discussions and Knowledge Gaps

1

Is AVIL-related nephrotic syndrome a reproducible entity beyond the three founding families?

KNOWLEDGE GAP avil_single_report_replication

Attached to

genetic#AVIL

All four variants come from one publication, ClinGen rates the relationship Limited, and the only animal model showed no renal phenotype. A 2026 Indonesian SRNS cohort lists AVIL among genes carrying a pathogenic or likely pathogenic variant, but its abstract gives no genotype or phenotype for that child.

Show evidence (2 references)

PMID:42420527 SUPPORT Human Clinical

"Among 60 children with primary SRNS, 9 subjects (15%) harbored pathogenic or likely pathogenic variants across 8 genes (CUBN, AVIL, TRPC6, INF2, COL4A4, LAMA5, INVS, and FGA)."

Possible further AVIL case; details are not in the abstract.

CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z SUPPORT REVIEW SYNTHESIS Other

"This curation includes four variants (frameshift and missense) identified in three probands, all described in a single publication (Rao et al., PMID: 29058690)."

ClinGen states the evidence base is a single publication.

⚙

Pathophysiology

5

Biallelic AVIL Loss of Function

Homozygous or compound heterozygous AVIL variants (p.Leu425Met homozygous; p.Arg135Gln with p.Phe656Valfs*7; p.Leu425Met with p.Arg446His) were found in three families with SRNS. ClinGen records loss of function as the proposed mechanism. Advillin's molecular function is actin filament binding; the activity is marked ABNORMAL rather than DECREASED because every tested patient allele loses filament bundling, but only the truncating allele loses F-actin binding itself.

AVIL hgnc:14188

Genetic context AVIL hgnc:14188 variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

actin filament binding (bundling-defective in patient alleles) GO:0051015 ⚠ ABNORMAL

Downstream

Loss of Advillin Actin-Bundling Activity

Show evidence (2 references)

PMID:29058690 SUPPORT Human Clinical

"we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS"

Founding report of biallelic AVIL variants in three SRNS families.

CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z SUPPORT REVIEW SYNTHESIS Other

"The proposed mechanism of pathogenicity is loss of function."

ClinGen Glomerulopathy GCEP summary of the disease mechanism.

Loss of Advillin Actin-Bundling Activity

Recombinant advillin carrying any of the three tested patient alleles fails to bundle F-actin in a low-speed sedimentation assay. Only the truncating p.Phe656Valfs*7 allele, which lacks the C-terminal F-actin-binding domain, also loses actin binding and severing; the two missense alleles keep normal severing.

actin filament bundle assembly GO:0051017 ↓ DECREASED

Downstream

Impaired PLCE1 Recruitment to Podocyte Lamellipodia Patient alleles weaken the AVIL-PLCE1 interaction and fail to rescue PLCE1-dependent DAG generation; whether loss of bundling itself, rather than another property of the mutant protein, causes the recruitment defect is not shown.

Show evidence (2 references)

PMID:29058690 SUPPORT In Vitro

"in all 3 AVIL mutants (Arg135Gln, Leu425Met, and Phe656Valfs*7) that represented the mutations found in patients with SRNS, a majority of the actin filaments now appeared in the supernatant (S) fraction, demonstrating a severe defect in actin bundling."

Sedimentation assay showing loss of bundling for every tested patient allele.

PMID:29058690 SUPPORT In Vitro

"Whereas the WT AVIL and 2 mutants representing missense alleles showed normal actin- severing function, the truncating mutant exhibited a complete loss of the actin-severing ability of AVIL"

Severing loss is restricted to the truncating allele.

Impaired PLCE1 Recruitment to Podocyte Lamellipodia

Advillin colocalizes with PLCE1 and the ARP2/3 complex at the podocyte periphery and co-immunoprecipitates with both. In AVIL-depleted podocytes, EGF stimulation fails to recruit PLCE1 to ARP3-rich lamellipodia and fails to raise diacylglycerol; wild-type AVIL rescues this, and the three patient alleles do not.

podocyte CL:0000653

PLCE1 hgnc:17175

phosphatidylinositol-4,5-bisphosphate phospholipase C activity GO:0004435 ↓ DECREASED

Experimental models

AVIL-depleted human podocyte line CELL LINE Knockdown blocks EGF-induced PLCE1 recruitment and DAG generation; patient alleles fail to rescue.

Downstream

Reduced Podocyte Migration PLCE1 acts downstream of AVIL for migration: PLCE1 overexpression rescues the AVIL-knockdown migration defect, but AVIL overexpression does not rescue PLCE1 knockdown. Inhibiting ARP2/3 abrogates the increase in migration, placing lamellipodia formation downstream of both.

Show evidence (2 references)

PMID:29058690 SUPPORT In Vitro

"Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR)."

Knockdown phenotype in cultured human podocytes.

PMID:29058690 SUPPORT In Vitro

"These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants."

Rescue experiment ties the defect to the patient alleles.

Reduced Podocyte Migration

AVIL knockdown lowers the podocyte migration rate in culture and reduces peripheral actin stress fibers, and the patient alleles fail to rescue it. Knockdown did not significantly change overall podocyte morphology. The authors treat migration rate as an established intermediate phenotype of monogenic SRNS; it is a cell-culture readout, and how it maps onto foot process failure in vivo is not shown for AVIL.

podocyte CL:0000653

podocyte cell migration GO:0090521 ↓ DECREASED stress fiber assembly GO:0043149 ↓ DECREASED

Experimental models

AVIL-depleted human podocyte line CELL LINE Migration rate falls after AVIL knockdown.

Downstream

Podocyte Injury and Glomerular Filtration Barrier Failure The link from a cell-culture migration defect to in vivo foot process effacement is inferred from its use as an intermediate phenotype across monogenic SRNS, not demonstrated for AVIL.

Show evidence (1 reference)

PMID:29058690 SUPPORT In Vitro

"Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR)."

Reduced migration rate after AVIL knockdown.

Podocyte Injury and Glomerular Filtration Barrier Failure

Electron microscopy in the homozygous p.Leu425Met patient showed diffuse foot process effacement, and both biopsied patients had diffuse mesangial sclerosis. Disruption of the podocyte layer of the glomerular filtration barrier produces nephrotic-range proteinuria.

podocyte CL:0000653

Animal models

Zebrafish avil CRISPR knockdown Zebrafish fails to recapitulate No larval edema, the usual zebrafish readout of a leaky glomerular filter.

Downstream

Podocyte Foot Process Effacement

Proteinuria Loss of the podocyte layer of the filtration barrier allows protein into the urine.

Diffuse Mesangial Sclerosis Diffuse mesangial sclerosis accompanies the podocyte injury in both biopsied patients; how podocyte failure leads to mesangial sclerosis is not shown for AVIL.

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"Transmission elec- tron microscopy (TEM) image from individual A2438_22 showed diffuse foot process effacement"

Ultrastructural podocyte injury in a patient.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

12

Ear 1

Hearing Impairment HP:0000365

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"Individual A2438_22 had severe SRNS combined with deafness, cataracts, microcephaly, and intellec- tual disability."

Extrarenal features in the homozygous patient.

Eye 2

Retinal Dystrophy HP:0000556

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"Individual A913_21 had severe NS combined with retinal dystrophy and pervasive refusal syndrome."

Extrarenal feature in one patient.

Cataract HP:0000518

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"Individual A2438_22 had severe SRNS combined with deafness, cataracts, microcephaly, and intellec- tual disability."

Extrarenal features in the homozygous patient.

Genitourinary 5

Proteinuria HP:0000093

Sequelae: Nephrotic Syndrome Generalized Edema

Show evidence (1 reference)

CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z SUPPORT REVIEW SYNTHESIS Other

"Nephrotic syndrome type 21 (congenital nephrotic syndrome) is characterized by significant proteinuria during the first months or years of life, leading to generalized edema."

ClinGen summary of the early-onset proteinuria.

Nephrotic Syndrome Steroid-resistant nephrotic syndrome HP:0012588

Onset: INFANTILE

Sequelae: Kidney Failure

Show evidence (2 references)

PMID:29058690 SUPPORT Human Clinical

"The 2 individuals manifested signs of NS before 1 year of age and progressed to ESRD before 3 years of age"

Infantile onset in both patients with clinical detail.

CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z SUPPORT REVIEW SYNTHESIS Other

"Nephrotic syndrome type 21 (congenital nephrotic syndrome) is characterized by significant proteinuria during the first months or years of life, leading to generalized edema."

ClinGen summary of the presentation.

Diffuse Mesangial Sclerosis HP:0001967

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"The renal histological analyses for individuals A2438_22 and A913_21 revealed diffuse mesangial sclerosis (DMS)"

Biopsy finding in both biopsied patients.

Podocyte Foot Process Effacement HP:0031266

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"Transmission elec- tron microscopy (TEM) image from individual A2438_22 showed diffuse foot process effacement"

Electron microscopy finding in one patient.

Kidney Failure Stage 5 chronic kidney disease HP:0003774

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"The 2 individuals manifested signs of NS before 1 year of age and progressed to ESRD before 3 years of age"

Early progression to end-stage kidney disease.

Head and Neck 1

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"Individual A2438_22 had severe SRNS combined with deafness, cataracts, microcephaly, and intellec- tual disability."

Extrarenal features in the homozygous patient.

Metabolism 1

Generalized Edema HP:0007430

Show evidence (1 reference)

CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z SUPPORT REVIEW SYNTHESIS Other

"Nephrotic syndrome type 21 (congenital nephrotic syndrome) is characterized by significant proteinuria during the first months or years of life, leading to generalized edema."

ClinGen summary describes generalized edema following proteinuria.

Nervous System 1

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"Individual A2438_22 had severe SRNS combined with deafness, cataracts, microcephaly, and intellec- tual disability."

Extrarenal features in the homozygous patient.

Growth 1

Short Stature HP:0004322

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Microcephaly, short stature, retinal dystrophy, cataracts, deafness"

GeneReviews lists the AVIL syndromic features, including short stature.

🧬

Genetic Associations

1

AVIL

Gene: AVIL hgnc:14188

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"We thereby identified recessive mutations in AVIL as a cause of recessive NS"

Gene-disease assertion from the founding report.

Variants (4)

c.1273C>A p.Leu425Met

Homozygous in the index patient of a consanguineous Turkish family (A2438_22), and compound heterozygous with p.Arg446His in an unrelated Turkish patient (A2647_21). Located in the GH4 gelsolin-homology domain; abolishes actin bundling and weakens the PLCE1 interaction in vitro.

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"we detected a homozygous missense mutation (c.1273C>A; p.Leu425Met"

Variant identified by homozygosity mapping and exome sequencing in the index family.

c.404G>A p.Arg135Gln

Compound heterozygous in trans with p.Phe656Valfs*7 in a UK patient (A913_21). Located in the GH2 domain; abolishes actin bundling in vitro.

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"we detected 2 compound heterozygous mutations in AVIL: c.404G>A (p.Arg135Gln) and c.1964dupT"

Variant pair found by resequencing an SRNS cohort.

c.1964dupT p.Phe656Valfs*7

Frameshift in trans with p.Arg135Gln (phase confirmed by TA cloning). The truncated protein lacks the C-terminal F-actin-binding region and loses actin binding, bundling and severing.

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"it was found that the compound heterozygous mutations were in trans"

Phase of the UK patient's two variants.

c.1337G>A p.Arg446His

Compound heterozygous with p.Leu425Met in a Turkish patient (A2647_21); parental DNA was not available, so phase was not assessed. Not functionally tested.

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"we detected 2 compound heterozygous mutations in AVIL: c.1337G>A (p.Arg446His) and c.1273C>A (p.Leu425Met)"

Variant pair in the third family.

💊

Medical Actions

4

Kidney Transplantation

Action: kidney transplantation Ontology label: Kidney Transplantation NCIT:C15265

Platform: Surgery

Kidney transplantation corrects genetic SRNS generally. One AVIL patient received a transplant; the post-transplant course is not reported, and no AVIL-specific data on immunosuppression response exist.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"All genetic SRNS can be corrected with kidney transplantation."

GeneReviews overview statement covering genetic SRNS generally, including AVIL.

Kidney Replacement Therapy

Action: kidney replacement therapy Ontology label: Renal Replacement Therapy NCIT:C126400

Platform: Device

Dialysis bridges to transplantation when kidney failure arrives in infancy or early childhood, as it did by age 3 in both AVIL patients with clinical detail. Dialysis use in these patients is not reported.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Kidney replacement therapy including preemptive transplantation in selected disorders"

GeneReviews management of kidney failure in genetic SRNS.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counseling on the 25% recurrence risk for sibs of an affected child, and carrier testing of relatives.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic"

Recurrence risk that genetic counseling conveys for autosomal recessive genetic SRNS.

ACE Inhibitor Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: ACE inhibitor NCIT:C247

Platform: Small molecule

The homozygous p.Leu425Met patient was treated with an angiotensin-converting enzyme inhibitor (Table 1, "ACEI"); no response or outcome is reported, and she reached kidney failure at 22 months.

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"SRNS ACEI DMS Deafness, cataract, microcephaly, intellectual disability, short stature"

Table 1 row for A2438_22 records ACE-inhibitor treatment (ACEI, angiotensin-converting enzyme inhibitor).

🔬

Diagnosis

2

Molecular Genetic Testing

Biallelic AVIL variants are identified by a nephrotic-syndrome multigene panel or by exome sequencing, with parental testing to confirm phase. Panel content varies, so inclusion of this rare gene should be checked. Because ClinGen rates the gene Limited, an AVIL finding should be interpreted cautiously.

molecular genetic testing NCIT:C15709

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Molecular genetic testing ... can include a combination of ... targeted testing (single-gene testing or ... ) and comprehensive ... testing"

GeneReviews describes gene-targeted and comprehensive genomic testing for genetic SRNS; the linked terms in the HTML are elided.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Some panels may not include newly discovered and/or rare genes associated with genetic SRNS."

AVIL is a rare gene, so panel coverage should be checked.

PMID:29058690 SUPPORT Human Clinical

"we examined a worldwide cohort of approximately 800 individuals with SRNS by exon resequencing of all 19 AVIL-coding exons"

Two of the three families were found by resequencing AVIL in an SRNS cohort.

Kidney Biopsy

Shows diffuse mesangial sclerosis, with diffuse foot process effacement on electron microscopy. It identifies the lesion, not the gene.

kidney biopsy NCIT:C51699

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"The renal histological analyses for individuals A2438_22 and A913_21 revealed diffuse mesangial sclerosis (DMS)"

Biopsy findings in both biopsied patients.

📊

Prevalence

1

Worldwide (published cases)

Cases In Literature Ultra Rare

Three families in the founding report: a consanguineous Turkish family (index), a UK patient and a second Turkish patient, the latter two found by resequencing AVIL in about 800 individuals with SRNS. A 2026 Indonesian SRNS cohort lists AVIL among its diagnostic genes without per-patient detail in the abstract.

Show evidence (1 reference)

PMID:29058690 SUPPORT Human Clinical

"In total, we detected 4 different homozygous or compound heterozygous mutations of AVIL in 3 families affected by NS"

The only published case series.

🧫

Experimental Models

1

AVIL-depleted human podocyte line CELL_LINE

Cultured human podocytes with AVIL shRNA or siRNA knockdown, rescued with wild-type or patient-allele constructs; co-immunoprecipitation was done in HEK293T cells.

Publication

PMID:29058690

Pathograph links

Impaired PLCE1 Recruitment to Podocyte Lamellipodia recapitulates fidelity: moderate observes: cellular Knockdown blocks EGF-induced PLCE1 recruitment and DAG generation; patient alleles fail to rescue.

Limitations: Immortalized podocytes in two dimensions with knockdown rather than endogenous patient alleles; the mutant proteins were tested by overexpression.

Show evidence (1 reference)

PMID:29058690 SUPPORT In Vitro

"These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants."

Rescue design links the cellular defect to the patient alleles.

Reduced Podocyte Migration recapitulates fidelity: low observes: cellular Migration rate falls after AVIL knockdown.

Limitations: Migration rate is a cell-culture proxy; its correspondence to foot process maintenance in vivo is assumed from other monogenic SRNS genes rather than shown for AVIL.

Show evidence (1 reference)

PMID:29058690 SUPPORT In Vitro

"Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR)."

Migration readout in the knockdown line.

🐁

Animal Models

1

Zebrafish avil CRISPR knockdown

The founding report generated a CRISPR avil knockdown in zebrafish to look for a renal phenotype; initial experiments showed no larval edema.

Species

Zebrafish

Genotype

avil CRISPR knockdown

Publication

PMID:29058690

Pathograph links

Podocyte Injury and Glomerular Filtration Barrier Failure fails to recapitulate fidelity: low observes: organism No larval edema, the usual zebrafish readout of a leaky glomerular filter.

Limitations: Reported as initial experiments only, without glomerular histology, ultrastructure or proteinuria measurement. The authors note that earlier positive zebrafish models of nephrotic syndrome genes relied on morpholinos, whose phenotypes often fail to reproduce in stable mutants, so a negative CRISPR result does not show that AVIL is dispensable for the zebrafish filter.

Show evidence (1 reference)

PMID:29058690 SUPPORT Model Organism

"we also generated a CRISPR model of Avil knockdown in zebrafish, but our initial experiments did not show a larval edema phenotype"

Negative result for the renal phenotype in the only reported animal model.

{ }

Source YAML

click to show

name: Nephrotic Syndrome Type 21
description: >-
  Autosomal recessive steroid-resistant nephrotic syndrome caused by biallelic loss-of-function variants in AVIL, which
  encodes advillin, a gelsolin/villin-family actin-regulatory protein expressed in podocytes. The founding report described
  four variants in three families. Patient alleles abolish actin bundling, and the truncating allele also loses actin
  binding and severing. In cultured human podocytes advillin interacts with PLCE1 and the ARP2/3 complex, and its loss
  prevents recruitment of PLCE1 to lamellipodia, blocks EGF-induced diacylglycerol generation and slows podocyte
  migration. The two biopsied patients had diffuse mesangial sclerosis, onset of nephrotic syndrome in the first year of
  life and kidney failure by age 3; extrarenal features included retinal dystrophy, deafness, cataract, microcephaly,
  intellectual disability and short stature. ClinGen classifies the gene-disease relationship as Limited.
category: Mendelian
disease_term:
  preferred_term: nephrotic syndrome, type 21
  term:
    id: MONDO:0032826
    label: nephrotic syndrome, type 21
synonyms:
- NPHS21
- AVIL-related nephrotic syndrome
- nephrotic syndrome caused by mutation in AVIL
creation_date: "2026-10-15T16:00:00Z"
parents:
- Familial Idiopathic Steroid-Resistant Nephrotic Syndrome
classifications:
  harrisons_chapter:
  - classification_value: KIDNEY_URINARY_TRACT
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
references:
- reference: PMID:34436835
  title: Genetic Steroid-Resistant Nephrotic Syndrome Overview.
  tags:
  - GeneReviews
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
  title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
prevalence:
- population: Worldwide (published cases)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three families in the founding report: a consanguineous Turkish family (index), a UK patient and a second Turkish
    patient, the latter two found by resequencing AVIL in about 800 individuals with SRNS. A 2026 Indonesian SRNS cohort
    lists AVIL among its diagnostic genes without per-patient detail in the abstract.
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, we detected 4 different homozygous or compound heterozygous mutations of AVIL in 3 families affected by NS
    explanation: The only published case series.
pathophysiology:
- name: Biallelic AVIL Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous AVIL variants (p.Leu425Met homozygous; p.Arg135Gln with p.Phe656Valfs*7;
    p.Leu425Met with p.Arg446His) were found in three families with SRNS. ClinGen records loss of function as the
    proposed mechanism. Advillin's molecular function is actin filament binding; the activity is marked ABNORMAL
    rather than DECREASED because every tested patient allele loses filament bundling, but only the truncating allele
    loses F-actin binding itself.
  genes:
  - preferred_term: AVIL
    term:
      id: hgnc:14188
      label: AVIL
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    gene:
      preferred_term: AVIL
      term:
        id: hgnc:14188
        label: AVIL
  molecular_functions:
  - preferred_term: actin filament binding (bundling-defective in patient alleles)
    modifier: ABNORMAL
    term:
      id: GO:0051015
      label: actin filament binding
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated
      families with SRNS
    explanation: Founding report of biallelic AVIL variants in three SRNS families.
  - reference: CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z
    reference_title: "AVIL / nephrotic syndrome, type 21 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The proposed mechanism of pathogenicity is loss of function.
    explanation: ClinGen Glomerulopathy GCEP summary of the disease mechanism.
  downstream:
  - target: Loss of Advillin Actin-Bundling Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also
        disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing.
      explanation: All three tested patient alleles lose actin bundling in vitro.
- name: Loss of Advillin Actin-Bundling Activity
  biological_scale: MOLECULAR
  description: >-
    Recombinant advillin carrying any of the three tested patient alleles fails to bundle F-actin in a low-speed
    sedimentation assay. Only the truncating p.Phe656Valfs*7 allele, which lacks the C-terminal F-actin-binding domain,
    also loses actin binding and severing; the two missense alleles keep normal severing.
  biological_processes:
  - preferred_term: actin filament bundle assembly
    modifier: DECREASED
    term:
      id: GO:0051017
      label: actin filament bundle assembly
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      in all 3 AVIL mutants (Arg135Gln, Leu425Met, and Phe656Valfs*7) that represented the mutations found in patients
      with SRNS, a majority of the actin filaments now appeared in the supernatant (S) fraction, demonstrating a severe
      defect in actin bundling.
    explanation: Sedimentation assay showing loss of bundling for every tested patient allele.
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Whereas the WT AVIL and 2 mutants representing missense alleles showed normal actin- severing function, the
      truncating mutant exhibited a complete loss of the actin-severing ability of AVIL
    explanation: Severing loss is restricted to the truncating allele.
  downstream:
  - target: Impaired PLCE1 Recruitment to Podocyte Lamellipodia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Patient alleles weaken the AVIL-PLCE1 interaction and fail to rescue PLCE1-dependent DAG generation; whether loss
      of bundling itself, rather than another property of the mutant protein, causes the recruitment defect is not shown.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We showed that the mutants Leu425Met and Phe656Valfs*7 , reflecting the alleles found in the patients with NS,
        weakened this interaction
      explanation: Two patient alleles weaken the AVIL-PLCE1 co-immunoprecipitation in HEK293T cells.
- name: Impaired PLCE1 Recruitment to Podocyte Lamellipodia
  biological_scale: CELLULAR
  description: >-
    Advillin colocalizes with PLCE1 and the ARP2/3 complex at the podocyte periphery and co-immunoprecipitates with both.
    In AVIL-depleted podocytes, EGF stimulation fails to recruit PLCE1 to ARP3-rich lamellipodia and fails to raise
    diacylglycerol; wild-type AVIL rescues this, and the three patient alleles do not.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  genes:
  - preferred_term: PLCE1
    term:
      id: hgnc:17175
      label: PLCE1
  molecular_functions:
  - preferred_term: phosphatidylinositol-4,5-bisphosphate phospholipase C activity
    modifier: DECREASED
    term:
      id: GO:0004435
      label: phosphatidylinositol-4,5-bisphosphate phospholipase C activity
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of
      PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and
      attenuated the podocyte migration rate (PMR).
    explanation: Knockdown phenotype in cultured human podocytes.
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived
      AVIL mutants.
    explanation: Rescue experiment ties the defect to the patient alleles.
  downstream:
  - target: Reduced Podocyte Migration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      PLCE1 acts downstream of AVIL for migration: PLCE1 overexpression rescues the AVIL-knockdown migration defect, but
      AVIL overexpression does not rescue PLCE1 knockdown. Inhibiting ARP2/3 abrogates the increase in migration,
      placing lamellipodia formation downstream of both.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we observed that the decreased PMR upon knockdown of AVIL was rescued by overex- pression of human PLCE1
      explanation: Epistasis experiment placing PLCE1 downstream of AVIL in podocyte migration.
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia
        formation occurs downstream of AVIL and PLCE1 function.
      explanation: ARP2/3 inhibition places lamellipodia formation downstream of AVIL and PLCE1.
- name: Reduced Podocyte Migration
  biological_scale: CELLULAR
  description: >-
    AVIL knockdown lowers the podocyte migration rate in culture and reduces peripheral actin stress fibers, and the
    patient alleles fail to rescue it. Knockdown did not significantly change overall podocyte morphology. The authors treat
    migration rate as an established intermediate phenotype of monogenic SRNS; it is a cell-culture readout, and how it
    maps onto foot process failure in vivo is not shown for AVIL.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: podocyte cell migration
    modifier: DECREASED
    term:
      id: GO:0090521
      label: podocyte cell migration
  - preferred_term: stress fiber assembly
    modifier: DECREASED
    term:
      id: GO:0043149
      label: stress fiber assembly
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of
      PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and
      attenuated the podocyte migration rate (PMR).
    explanation: Reduced migration rate after AVIL knockdown.
  downstream:
  - target: Podocyte Injury and Glomerular Filtration Barrier Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The link from a cell-culture migration defect to in vivo foot process effacement is inferred from its use as an
      intermediate phenotype across monogenic SRNS, not demonstrated for AVIL.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: >-
        a defect in the podocyte migration rate (PMR) in cell culture has been established as a reliable intermedi- ate
        phenotype in monogenic forms of SRNS
      explanation: The authors' rationale for treating the migration defect as a proxy for podocyte disease.
- name: Podocyte Injury and Glomerular Filtration Barrier Failure
  biological_scale: TISSUE
  description: >-
    Electron microscopy in the homozygous p.Leu425Met patient showed diffuse foot process effacement, and both biopsied
    patients had diffuse mesangial sclerosis. Disruption of the podocyte layer of the glomerular filtration barrier
    produces nephrotic-range proteinuria.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transmission elec- tron microscopy (TEM) image from individual A2438_22 showed diffuse foot process effacement
    explanation: Ultrastructural podocyte injury in a patient.
  downstream:
  - target: Podocyte Foot Process Effacement
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Transmission elec- tron microscopy (TEM) image from individual A2438_22 showed diffuse foot process effacement
      explanation: Foot process effacement is the ultrastructural form of podocyte injury seen in a patient.
  - target: Proteinuria
    causal_link_type: DIRECT
    description: Loss of the podocyte layer of the filtration barrier allows protein into the urine.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
      reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        affects the establishment and maintenance of the glomerular filtration barrier. The glomerular filtration barrier
        comprises podocytes, the glomerular basement membrane, and fenestrated endothelial cells.
      explanation: GeneReviews frames genetic SRNS as failure of the glomerular filtration barrier.
  - target: Diffuse Mesangial Sclerosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Diffuse mesangial sclerosis accompanies the podocyte injury in both biopsied patients; how podocyte failure leads to
      mesangial sclerosis is not shown for AVIL.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The renal histological analyses for individuals A2438_22 and A913_21 revealed diffuse mesangial sclerosis (DMS)
      explanation: Co-occurring histology in the biopsied patients.
phenotypes:
- category: Renal
  name: Proteinuria
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z
    reference_title: "AVIL / nephrotic syndrome, type 21 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Nephrotic syndrome type 21 (congenital nephrotic syndrome) is characterized by significant proteinuria during the
      first months or years of life, leading to generalized edema.
    explanation: ClinGen summary of the early-onset proteinuria.
  sequelae:
  - target: Nephrotic Syndrome
  - target: Generalized Edema
- category: Renal
  name: Generalized Edema
  phenotype_term:
    preferred_term: Generalized edema
    term:
      id: HP:0007430
      label: Generalized edema
  evidence:
  - reference: CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z
    reference_title: "AVIL / nephrotic syndrome, type 21 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Nephrotic syndrome type 21 (congenital nephrotic syndrome) is characterized by significant proteinuria during the
      first months or years of life, leading to generalized edema.
    explanation: ClinGen summary describes generalized edema following proteinuria.
- category: Renal
  name: Nephrotic Syndrome
  description: >-
    Steroid-resistant nephrotic syndrome, reported in all three families. In the two patients with clinical detail, signs
    began in the first year of life.
  phenotype_term:
    preferred_term: Steroid-resistant nephrotic syndrome
    term:
      id: HP:0012588
      label: Steroid-resistant nephrotic syndrome
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 2 individuals manifested signs of NS before 1 year of age and progressed to ESRD before 3 years of age
    explanation: Infantile onset in both patients with clinical detail.
  - reference: CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z
    reference_title: "AVIL / nephrotic syndrome, type 21 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Nephrotic syndrome type 21 (congenital nephrotic syndrome) is characterized by significant proteinuria during the
      first months or years of life, leading to generalized edema.
    explanation: ClinGen summary of the presentation.
  sequelae:
  - target: Kidney Failure
- category: Renal
  name: Diffuse Mesangial Sclerosis
  description: Kidney biopsy in both biopsied patients showed diffuse mesangial sclerosis.
  phenotype_term:
    preferred_term: Diffuse mesangial sclerosis
    term:
      id: HP:0001967
      label: Diffuse mesangial sclerosis
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The renal histological analyses for individuals A2438_22 and A913_21 revealed diffuse mesangial sclerosis (DMS)
    explanation: Biopsy finding in both biopsied patients.
- category: Renal
  name: Podocyte Foot Process Effacement
  phenotype_term:
    preferred_term: Podocyte foot process effacement
    term:
      id: HP:0031266
      label: Podocyte foot process effacement
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transmission elec- tron microscopy (TEM) image from individual A2438_22 showed diffuse foot process effacement
    explanation: Electron microscopy finding in one patient.
- category: Renal
  name: Kidney Failure
  description: >-
    Both patients with clinical detail reached kidney failure by age 3 (at 22 months and at 3 years); one received a
    kidney transplant.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 2 individuals manifested signs of NS before 1 year of age and progressed to ESRD before 3 years of age
    explanation: Early progression to end-stage kidney disease.
- category: Ophthalmological
  name: Retinal Dystrophy
  description: >-
    Reported in the compound heterozygous UK patient (p.Arg135Gln / p.Phe656Valfs*7), who also had pervasive refusal
    syndrome, for which HPO has no term.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual A913_21 had severe NS combined with retinal dystrophy and pervasive refusal syndrome.
    explanation: Extrarenal feature in one patient.
- category: Auditory
  name: Hearing Impairment
  description: >-
    Deafness was reported in the homozygous p.Leu425Met patient; its type is not stated. This patient is from a
    consanguineous family with about 94 Mb of homozygosity, so a second recessive cause of her extrarenal features is
    not excluded; the same caveat applies to her cataract, microcephaly, intellectual disability and short stature.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual A2438_22 had severe SRNS combined with deafness, cataracts, microcephaly, and intellec- tual disability.
    explanation: Extrarenal features in the homozygous patient.
- category: Ophthalmological
  name: Cataract
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual A2438_22 had severe SRNS combined with deafness, cataracts, microcephaly, and intellec- tual disability.
    explanation: Extrarenal features in the homozygous patient.
- category: Neurological
  name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual A2438_22 had severe SRNS combined with deafness, cataracts, microcephaly, and intellec- tual disability.
    explanation: Extrarenal features in the homozygous patient.
- category: Neurological
  name: Intellectual Disability
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual A2438_22 had severe SRNS combined with deafness, cataracts, microcephaly, and intellec- tual disability.
    explanation: Extrarenal features in the homozygous patient.
- category: Growth
  name: Short Stature
  description: Listed for the homozygous p.Leu425Met patient in the founding report's Table 1.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Microcephaly, short stature, retinal dystrophy, cataracts, deafness
    explanation: GeneReviews lists the AVIL syndromic features, including short stature.
genetic:
- name: AVIL
  gene_term:
    preferred_term: AVIL
    term:
      id: hgnc:14188
      label: AVIL
  notes: >-
    The founding report proposed the symbol NPHS25 for this disorder; OMIM (618594) and MONDO list it as nephrotic
    syndrome type 21. All four reported variants come from one publication. relationship_type is left unset because
    CAUSATIVE is defined as Definitive or Strong validity and ClinGen rates AVIL Limited.
  variants:
  - name: c.1273C>A p.Leu425Met
    description: >-
      Homozygous in the index patient of a consanguineous Turkish family (A2438_22), and compound heterozygous with
      p.Arg446His in an unrelated Turkish patient (A2647_21). Located in the GH4 gelsolin-homology domain; abolishes actin
      bundling and weakens the PLCE1 interaction in vitro.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: we detected a homozygous missense mutation (c.1273C>A; p.Leu425Met
      explanation: Variant identified by homozygosity mapping and exome sequencing in the index family.
  - name: c.404G>A p.Arg135Gln
    description: >-
      Compound heterozygous in trans with p.Phe656Valfs*7 in a UK patient (A913_21). Located in the GH2 domain; abolishes
      actin bundling in vitro.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we detected 2 compound heterozygous mutations in AVIL: c.404G>A (p.Arg135Gln) and c.1964dupT"
      explanation: Variant pair found by resequencing an SRNS cohort.
  - name: c.1964dupT p.Phe656Valfs*7
    description: >-
      Frameshift in trans with p.Arg135Gln (phase confirmed by TA cloning). The truncated protein lacks the C-terminal
      F-actin-binding region and loses actin binding, bundling and severing.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: it was found that the compound heterozygous mutations were in trans
      explanation: Phase of the UK patient's two variants.
  - name: c.1337G>A p.Arg446His
    description: >-
      Compound heterozygous with p.Leu425Met in a Turkish patient (A2647_21); parental DNA was not available, so phase was
      not assessed. Not functionally tested.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we detected 2 compound heterozygous mutations in AVIL: c.1337G>A (p.Arg446His) and c.1273C>A (p.Leu425Met)
      explanation: Variant pair in the third family.
  gene_disease_validity:
  - validity_classification: LIMITED
    classified_by: CLINGEN
    external_id: CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z
    evidence:
    - reference: CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z
      reference_title: "AVIL / nephrotic syndrome, type 21 (Limited)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "AVIL | HGNC:14188 | nephrotic syndrome, type 21 | MONDO:0032826 | AR | Limited"
      explanation: ClinGen Glomerulopathy GCEP classification.
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We thereby identified recessive mutations in AVIL as a cause of recessive NS
    explanation: Gene-disease assertion from the founding report.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z
    reference_title: "AVIL / nephrotic syndrome, type 21 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AVIL | HGNC:14188 | nephrotic syndrome, type 21 | MONDO:0032826 | AR | Limited"
    explanation: ClinGen records autosomal recessive inheritance.
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutation segregation was consis- tent with recessive inheritance when parental DNA was available
    explanation: Segregation in the founding families.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an
      asymptomatic
    explanation: GeneReviews recurrence risk for autosomal recessive genetic SRNS, which applies to AVIL.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Biallelic AVIL variants are identified by a nephrotic-syndrome multigene panel or by exome sequencing, with parental
    testing to confirm phase. Panel content varies, so inclusion of this rare gene should be checked. Because ClinGen
    rates the gene Limited, an AVIL finding should be interpreted cautiously.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Molecular genetic testing ... can include a combination of ... targeted testing (single-gene testing or ... ) and comprehensive ... testing
    explanation: >-
      GeneReviews describes gene-targeted and comprehensive genomic testing for genetic SRNS; the linked terms in the HTML
      are elided.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Some panels may not include newly discovered and/or rare genes associated with genetic SRNS.
    explanation: AVIL is a rare gene, so panel coverage should be checked.
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we examined a worldwide cohort of approximately 800 individuals with SRNS by exon resequencing of all 19 AVIL-coding
      exons
    explanation: Two of the three families were found by resequencing AVIL in an SRNS cohort.
- name: Kidney Biopsy
  description: >-
    Shows diffuse mesangial sclerosis, with diffuse foot process effacement on electron microscopy. It identifies the
    lesion, not the gene.
  diagnosis_term:
    preferred_term: kidney biopsy
    term:
      id: NCIT:C51699
      label: Kidney Biopsy
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The renal histological analyses for individuals A2438_22 and A913_21 revealed diffuse mesangial sclerosis (DMS)
    explanation: Biopsy findings in both biopsied patients.
treatments:
- name: Kidney Transplantation
  description: >-
    Kidney transplantation corrects genetic SRNS generally. One AVIL patient received a transplant; the post-transplant
    course is not reported, and no AVIL-specific data on immunosuppression response exist.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: kidney transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: All genetic SRNS can be corrected with kidney transplantation.
    explanation: GeneReviews overview statement covering genetic SRNS generally, including AVIL.
- name: Kidney Replacement Therapy
  description: >-
    Dialysis bridges to transplantation when kidney failure arrives in infancy or early childhood, as it did by age 3 in
    both AVIL patients with clinical detail. Dialysis use in these patients is not reported.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: kidney replacement therapy
    term:
      id: NCIT:C126400
      label: Renal Replacement Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Kidney replacement therapy including preemptive transplantation in selected disorders
    explanation: GeneReviews management of kidney failure in genetic SRNS.
- name: Genetic Counseling
  description: Counseling on the 25% recurrence risk for sibs of an affected child, and carrier testing of relatives.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an
      asymptomatic
    explanation: Recurrence risk that genetic counseling conveys for autosomal recessive genetic SRNS.
- name: ACE Inhibitor Therapy
  description: >-
    The homozygous p.Leu425Met patient was treated with an angiotensin-converting enzyme inhibitor (Table 1, "ACEI"); no
    response or outcome is reported, and she reached kidney failure at 22 months.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
  evidence:
  - reference: PMID:29058690
    reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SRNS ACEI DMS Deafness, cataract, microcephaly, intellectual disability, short stature
    explanation: Table 1 row for A2438_22 records ACE-inhibitor treatment (ACEI, angiotensin-converting enzyme inhibitor).
animal_models:
- name: Zebrafish avil CRISPR knockdown
  species: Zebrafish
  genotype: avil CRISPR knockdown
  publication: PMID:29058690
  description: >-
    The founding report generated a CRISPR avil knockdown in zebrafish to look for a renal phenotype; initial experiments
    showed no larval edema.
  modeled_mechanisms:
  - target: Podocyte Injury and Glomerular Filtration Barrier Failure
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: No larval edema, the usual zebrafish readout of a leaky glomerular filter.
    limitations: >-
      Reported as initial experiments only, without glomerular histology, ultrastructure or proteinuria measurement. The
      authors note that earlier positive zebrafish models of nephrotic syndrome genes relied on morpholinos, whose
      phenotypes often fail to reproduce in stable mutants, so a negative CRISPR result does not show that AVIL is
      dispensable for the zebrafish filter.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we also generated a CRISPR model of Avil knockdown in zebrafish, but our initial experiments did not show a larval
        edema phenotype
      explanation: Negative result for the renal phenotype in the only reported animal model.
experimental_models:
- name: AVIL-depleted human podocyte line
  experimental_model_type: CELL_LINE
  description: >-
    Cultured human podocytes with AVIL shRNA or siRNA knockdown, rescued with wild-type or patient-allele constructs;
    co-immunoprecipitation was done in HEK293T cells.
  publication: PMID:29058690
  modeled_mechanisms:
  - target: Impaired PLCE1 Recruitment to Podocyte Lamellipodia
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Knockdown blocks EGF-induced PLCE1 recruitment and DAG generation; patient alleles fail to rescue.
    limitations: >-
      Immortalized podocytes in two dimensions with knockdown rather than endogenous patient alleles; the mutant proteins
      were tested by overexpression.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived
        AVIL mutants.
      explanation: Rescue design links the cellular defect to the patient alleles.
  - target: Reduced Podocyte Migration
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Migration rate falls after AVIL knockdown.
    limitations: >-
      Migration rate is a cell-culture proxy; its correspondence to foot process maintenance in vivo is assumed from other
      monogenic SRNS genes rather than shown for AVIL.
    evidence:
    - reference: PMID:29058690
      reference_title: Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of
        PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and
        attenuated the podocyte migration rate (PMR).
      explanation: Migration readout in the knockdown line.
discussions:
- discussion_id: avil_single_report_replication
  kind: KNOWLEDGE_GAP
  prompt: Is AVIL-related nephrotic syndrome a reproducible entity beyond the three founding families?
  rationale: >-
    All four variants come from one publication, ClinGen rates the relationship Limited, and the only animal model showed
    no renal phenotype. A 2026 Indonesian SRNS cohort lists AVIL among genes carrying a pathogenic or likely pathogenic
    variant, but its abstract gives no genotype or phenotype for that child.
  attaches_to:
  - genetic#AVIL
  evidence:
  - reference: PMID:42420527
    reference_title: Genetic mutation patterns in Indonesian children with primary steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 60 children with primary SRNS, 9 subjects (15%) harbored pathogenic or likely pathogenic variants across 8
      genes (CUBN, AVIL, TRPC6, INF2, COL4A4, LAMA5, INVS, and FGA).
    explanation: Possible further AVIL case; details are not in the abstract.
  - reference: CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z
    reference_title: "AVIL / nephrotic syndrome, type 21 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      This curation includes four variants (frameshift and missense) identified in three probands, all described in a single
      publication (Rao et al., PMID: 29058690).
    explanation: ClinGen states the evidence base is a single publication.
notes: >-
  No dedicated GeneReviews chapter exists for this disorder; it is covered as one row of the Genetic Steroid-Resistant
  Nephrotic Syndrome Overview (PMID:34436835). The founding report describes a spectrum from early-onset disease with
  diffuse mesangial sclerosis to later-onset FSGS, by analogy with PLCE1 disease, but none of its AVIL patients is
  documented with FSGS, so FSGS is not recorded as a phenotype here.

📚

References & Deep Research

References

2

PMID:34436835

Genetic Steroid-Resistant Nephrotic Syndrome Overview.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/

Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Nephrotic_Syndrome_Type_21 · 2026-10-15T15:34:03Z · View source

New entry for AVIL-related autosomal recessive steroid-resistant nephrotic syndrome (MONDO:0032826), claimed in issue 14344. The evidence base is one founding paper (Rao et al. 2017, PMID:29058690, full text cached), the ClinGen Glomerulopathy GCEP record (Limited, AR), the GeneReviews Genetic SRNS Overview, and the abstract of a 2026 Indonesian SRNS cohort that lists AVIL without per-patient detail. Deep research: falcon was requested but failed with 503 Failed to authenticate; the client classed it as a temporary server error, so neither --fallback nor --fallback-provider claude_code handed over. claude_code was then run directly (research/Nephrotic_Syndrome_Type_21-deep-research-claude_code.md; 8/8 references resolved; one term mislabel was a harmless paraphrase of HP:0000007). preflight-dr confirmed the report is about AVIL; PLCE1 mentions are the interaction partner, not a second disease. relationship_type is left unset because CAUSATIVE requires Definitive or Strong validity. The zebrafish CRISPR knockdown is recorded as FAILS_TO_RECAPITULATE, and a KNOWLEDGE_GAP discussion records the single-publication basis. A parallel session drafted a duplicate entry for the same disease (issue 14345, closed as duplicate); its consanguinity caveat and GeneReviews PMID tag were folded in here and its files deleted. The ClinGen cache file was generated from a local gene_validity.csv export dated 2026-10-15, newer than the manifest pin; its Source line records that date. A fresh-context review pass was applied (variants structured, edge types weakened where intermediates are known or unshown, unsupported GO terms dropped, Kidney Transplantation bound to NCIT:C15265). Validation: just validate-disorders passes; 45/45 snippets verified; entity refs, causal targets and term cache integrity pass.

Claude Code ▸

Nephrotic Syndrome Type 21 (NPHS21; AVIL-related steroid-resistant nephrotic syndrome): research report

claude-haiku-5-5, claude-opus-5-5 13 citations 2026-10-15T11:22:54.077796

Reading the last cached reference, then checking for newer AVIL literature.

Nephrotic Syndrome Type 21 (NPHS21; AVIL-related steroid-resistant nephrotic syndrome): research report

Target: Nephrotic syndrome, type 21 (MONDO:0032826) · Category: Mendelian · Prepared: 2026-10-15

Evidence base caveat. Almost everything known about this disorder comes from one paper: Rao, Ashraf et al., J Clin Invest 2017 (PMID:29058690). It describes four variants in three probands from three families. ClinGen's 2024 re-curation states: "This curation includes four variants (frameshift and missense) identified in three probands, all described in a single publication (Rao et al., PMID: 29058690). No additional evidence is available in the literature." ClinGen classifies the gene–disease pair as Limited. One 2026 Indonesian cohort (PMID:42420527) lists AVIL among genes carrying a P/LP variant, but its abstract gives no per-patient detail. Many template sections therefore have no disease-specific data, and this report says so where that applies rather than borrowing from SRNS in general without saying so.

Quotes from PMID:29058690 are taken from the cached full text (references_cache/PMID_29058690.md). Quotes from ClinGen and GeneReviews come from the local cache files CGGV_assertion_04806c21-…md and url_…NBK573219_.md.

1. Disease information

Overview. NPHS21 is an autosomal recessive form of steroid-resistant nephrotic syndrome (SRNS). It is caused by biallelic loss-of-function variants in AVIL, which encodes advillin, an actin-regulatory protein in the gelsolin/villin family. In the two probands with clinical detail, nephrotic syndrome began in the first year of life, biopsy showed diffuse mesangial sclerosis (DMS), and kidney failure followed before age 3. Some patients also had extrarenal features: retinal dystrophy, deafness, cataract, microcephaly, intellectual disability and short stature.

PMID:29058690: "we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS."
ClinGen: "Nephrotic syndrome type 21 (congenital nephrotic syndrome) is characterized by significant proteinuria during the first months or years of life, leading to generalized edema."

Identifiers

System	ID	Note
MONDO	MONDO:0032826 "nephrotic syndrome, type 21"	Verified against the ClinGen row
OMIM (phenotype)	618594	Cited by ClinGen and GeneReviews
OMIM (gene)	*613397 ADVILLIN; AVIL	OMIM
HGNC	HGNC:14188 (written `hgnc:14188` in dismech)
ClinGen GCEP	CGGV:assertion_04806c21-071c-4a74-96c2-ab89ef5ba0e0-2024-08-27T180000.000Z (CCID:008997)	AR, Limited, SOP10, re-evaluated 2024-08-27
Orphanet	No disorder-specific ORPHA code found	Likely falls under a generic "genetic SRNS" grouping. Not verified, so do not bind
ICD-10-CM	N04.x (nephrotic syndrome), e.g. N04.1/N04.9	Non-specific
ICD-11	GB41 (nephrotic syndrome)	Non-specific
MeSH	D009404 Nephrotic Syndrome	Non-specific

Synonyms. NPHS21; AVIL-related nephrotic syndrome; nephrotic syndrome caused by mutation in AVIL. The founding paper proposed "NPHS25": "We thereby identified recessive mutations in AVIL as a cause of recessive NS and introduce the term 'NPHS25' for this variant of monogenic SRNS." OMIM and MONDO number it type 21. Expect this discrepancy in the literature.

Data provenance. All phenotype data are individual-patient data from research sequencing (3 probands), compiled by aggregate resources (OMIM, ClinGen, GeneReviews). There are no EHR-derived or registry data.

2. Etiology

Cause. Germline biallelic (homozygous or compound heterozygous) AVIL variants. Proposed mechanism (ClinGen): "The proposed mechanism of pathogenicity is loss of function."
Genetic risk factors. Parental consanguinity: the homozygous index family (A2438, Turkey) was consanguineous. Two of the three probands are of Turkish descent.
Environmental risk factors. None known.
Protective factors. None known, genetic or environmental.
Modifier genes. None reported. The extrarenal phenotype varies between probands (retinal dystrophy in one; deafness, cataract, microcephaly and intellectual disability in another), but the paper did not exclude a second diagnosis in these consanguineous families. Treat the syndromic features as attributed, not proven.
Gene–environment interactions. None described. In the podocyte model, EGF stimulation partly compensates for AVIL knockdown (see §6), but that is a cell-culture finding, not a clinical exposure.

3. Phenotypes

The denominator is tiny: the frequencies below are counts out of 3 probands, and clinical detail exists for only 2.

Phenotype	Suggested HPO	Type	Onset / course	Frequency	Source
Steroid-resistant nephrotic syndrome	HP:0012588 Steroid-resistant nephrotic syndrome	Clinical/lab	Infantile (<1 yr); rapidly progressive	3/3	PMID:29058690
Nephrotic-range proteinuria	HP:0000093 Proteinuria (verify)	Lab	Infancy	3/3 (implied)	ClinGen summary
Generalized edema	HP:0007430 Generalized edema (verify)	Sign	Infancy	Not individually reported	ClinGen summary
Diffuse mesangial sclerosis	HP:0001967 Diffuse mesangial sclerosis	Histopathology	—	2/2 biopsied	PMID:29058690
Podocyte foot process effacement	HP:0031266 Podocyte foot process effacement	Ultrastructure	—	1/1 with EM	PMID:29058690
Kidney failure	HP:0003774 Stage 5 chronic kidney disease	Clinical	22 months and 3 years	2/2 with data	PMID:29058690
Retinal dystrophy	HP:0000556 Retinal dystrophy	Sign	NR	1/3 (A913_21, UK)	PMID:29058690
Deafness (type not stated)	HP:0000365 Hearing impairment	Sign	NR	1/3 (A2438_22)	PMID:29058690
Cataract	HP:0000518 Cataract	Sign	NR	1/3	PMID:29058690
Microcephaly	HP:0000252 Microcephaly	Sign	NR	1/3	PMID:29058690
Intellectual disability	HP:0001249 Intellectual disability	Behavioral/cognitive	NR	1/3	PMID:29058690
Short stature	HP:0004322 Short stature	Growth	NR	1/3 (Table 1)	PMID:29058690 Table 1; GeneReviews
"Pervasive refusal syndrome"	No good HPO term; leave free-text or omit	Behavioral	NR	1/3	PMID:29058690

Key quotes (PMID:29058690): - "The renal histological analyses for individuals A2438_22 and A913_21 revealed diffuse mesangial sclerosis (DMS)" - "The 2 individuals manifested signs of NS before 1 year of age and progressed to ESRD before 3 years of age" - "Individual A2438_22 had severe SRNS combined with deafness, cataracts, microcephaly, and intellectual disability. Individual A913_21 had severe NS combined with retinal dystrophy and pervasive refusal syndrome." - The authors also describe a spectrum: "A spectrum ranging from severe early-onset NS with DMS to a later-onset form with FSGS was observed here, as has also been described in phospholipase C ϵ1 (PLCE1) mutations." The third proband (A2647_21) has no onset age or histology in Table 1, so the "later-onset FSGS" end of the spectrum is not documented for any specific AVIL patient. - GeneReviews' Genetic SRNS Overview (NBK573219) lists AVIL's extrarenal features as "Microcephaly, short stature, retinal dystrophy, cataracts, deafness, & DD (OMIM 618594)".

Quality of life. No disease-specific data. General pediatric SRNS and dialysis QoL literature applies only by extrapolation.

4. Genetic and molecular information

Causal gene. AVIL (advillin), 12q14.1, HGNC:14188, RefSeq NM_006576. It has six gelsolin homology (GH/S1–S6) domains and a C-terminal villin-type headpiece (HP).

Reported variants (all from PMID:29058690, Table 1)

Proband (origin)	Genotype	cDNA	Protein	Type	Domain	ExAC homozygotes
A2438_22 (Turkey, consanguineous)	Homozygous; segregates (M, P het)	c.1273C>A	p.Leu425Met	Missense	GH4	None (A = 5/120,708)
A913_21 (UK)	Compound het, confirmed in trans by TA cloning	c.404G>A + c.1964dupT	p.Arg135Gln + p.Phe656Valfs*7	Missense + frameshift	GH2; truncates S6+HP	None
A2647_21 (Turkey)	Compound het; phase not assessed (parents NA)	c.1273C>A + c.1337G>A	p.Leu425Met + p.Arg446His	Missense ×2	GH4	p.Arg446His not present in ExAC

ClinVar lists p.Arg446His (RCV000845156) for SRNS (ClinVar). Per-variant ACMG classifications in ClinVar were not reviewed for this report; check each before quoting a classification.
p.Leu425Met occurs in two unrelated Turkish probands. That suggests a possible founder allele, but no haplotype analysis was done.
Origin: germline. Functional class: loss of function (bundling lost for all alleles; binding and severing lost only for the truncating allele; see §6).
Gene–disease validity: ClinGen Limited (Genetic 3.1 + Experimental 2.0 = 5.1 points). From the ClinGen record: "This classification reflects the fact that the association has not yet been repeatedly demonstrated in both research and clinical diagnostic settings over time."
Replication. Fahlevi et al. 2026 (PMID:42420527) report that 9 of 60 Indonesian children with primary SRNS "harbored pathogenic or likely pathogenic variants across 8 genes (CUBN, AVIL, TRPC6, INF2, COL4A4, LAMA5, INVS, and FGA)". The abstract does not give the AVIL genotype, zygosity, phenotype, or whether "microcephaly with short stature" belongs to that child. Obtain the full text before using this as a second AVIL proband.
Modifier genes, epigenetics, chromosomal abnormalities. None reported. CNV analysis in the founding cohort found "no deleterious CNV."

5. Environmental information

There are no environmental, lifestyle or infectious factors. This is a monogenic disorder with infantile onset. Intercurrent infections and nephrotic complications (thrombosis, infection from hypogammaglobulinemia) are general features of nephrotic syndrome, not documented for AVIL patients.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic germline AVIL variants → advillin loses function. (Human genetic; mechanism per ClinGen.)
Loss of F-actin bundling by advillin. All three tested patient alleles (R135Q, L425M, F656Vfs7) bundle poorly in a low-speed sedimentation assay. Only the truncating allele also loses actin binding and severing. (In vitro, demonstrated.)*
"in all 3 AVIL mutants … a majority of the actin filaments now appeared in the supernatant (S) fraction, demonstrating a severe defect in actin bundling."
"Whereas the WT AVIL and 2 mutants representing missense alleles showed normal actin-severing function, the truncating mutant exhibited a complete loss of the actin-severing ability of AVIL"
Molecular-dynamics modelling suggests R135Q (GH2, near the type-2 Ca²⁺ site) and L425M (GH4, actin-binding α-helix) increase local flexibility (computational).
The interaction of advillin with PLCE1 and ARP2/3 is weakened. AVIL colocalizes with PLCE1 and ARP3 at the podocyte periphery and lamellipodia, and co-immunoprecipitates with PLCE1, ACTR2 and ACTR3. "the mutants Leu425Met and Phe656Valfs7 … weakened this interaction" (in vitro, HEK293T). Inferred step:* whether loss of bundling itself causes step 4, rather than some other property of the mutant protein, is not shown.
PLCE1 is not recruited to lamellipodia and does not produce DAG. On EGF stimulation, AVIL-depleted podocytes fail to recruit PLCE1 to ARP3-rich lamellipodia, and EGF-induced diacylglycerol (DAG) generation is blocked. Wild-type AVIL rescues this; none of the three patient alleles does. (In vitro, human immortalized podocytes.)
"Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants."
ARP2/3-dependent lamellipodia formation fails and podocyte migration rate falls. Epistasis places PLCE1 downstream of AVIL (PLCE1 overexpression rescues AVIL knockdown, but not the reverse) and ARP2/3 downstream of both (the inhibitor CK666 abolishes the pro-migratory effect). (In vitro.)
"this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function."
Podocyte foot-process effacement and glomerular filtration barrier failure. (Inferred.) The link from a culture migration defect to foot-process injury in vivo rests on PMR being used as an "intermediate phenotype" across monogenic SRNS. It has not been shown for AVIL: "a defect in the podocyte migration rate (PMR) in cell culture has been established as a reliable intermediate phenotype in monogenic forms of SRNS" (background statement). Human EM does show diffuse effacement in A2438_22.
Clinical result. Nephrotic-range proteinuria → hypoalbuminemia and edema → DMS → kidney failure in early childhood. (Human clinical, n = 2.)

Branch (unexplained). Extrarenal features (retina, lens, hearing, brain growth) are not mechanistically linked to AVIL. Advillin is otherwise known mainly from peripheral sensory neurons (see §15). There is no evidence connecting AVIL to the eye or inner ear.

Shared pathway. This chain converges on the PLCE1 axis. PLCE1 (NPHS3) causes DMS/FSGS SRNS with a similar early-onset spectrum, so NPHS21 belongs with the actin-cytoskeleton / Rho-GTPase cluster of podocytopathies.

Ontology suggestions

Concept	Term	Modifier
Actin filament bundle assembly	GO:0051017 actin filament bundle assembly	DECREASED
Actin filament binding	GO:0051015 actin filament binding	DECREASED (truncating allele)
Actin filament severing	GO:0051014 actin filament severing (verify label)	DECREASED (truncating only)
PLCE1 activity	GO:0004435 phosphatidylinositol-4,5-bisphosphate phospholipase C activity	DECREASED
Lamellipodium assembly	GO:0030032 lamellipodium assembly	DECREASED
Podocyte migration	GO:0090521 podocyte cell migration	DECREASED
Arp2/3 complex-mediated actin nucleation	GO:0034314 (verify)	—
Cell type	CL:0000653 podocyte	—
Interacting genes	PLCE1 hgnc:17175; ACTR2, ACTR3 (look up HGNC IDs)	—
Chemical	diacylglycerol, CHEBI:18035 (verify)	DECREASED

Not available for this disease: metabolomic, proteomic, transcriptomic, single-cell, spatial or CRISPR-screen data. There is no immune involvement; this is a primary podocytopathy and is not immune-mediated, which is consistent with steroid resistance.

7. Anatomical structures affected

Primary organ: kidney, specifically the glomerulus. Suggested terms: UBERON:0002113 kidney, UBERON:0000074 renal glomerulus; glomerular visceral epithelium / podocyte layer (look up the UBERON ID).
Cell: podocyte (CL:0000653). AVIL was detected in cultured human podocytes and in WT1-positive podocytes of 2-day-old rat glomeruli: "AVIL localized to the cytoplasm of podocytes in rat glomeruli."
Subcellular: lamellipodium (GO:0030027), actin cytoskeleton/stress fibers, focal adhesion (GO:0005925), cell cortex/periphery. Look up the GO CC IDs.
Secondary (in single patients): retina, lens, inner ear (auditory system), brain (microcephaly, intellectual disability).
Laterality: bilateral kidney involvement (systemic glomerular disease). Ocular laterality was not reported.

8. Temporal development

Onset: infantile (<12 months) in 2/2 with data. The index homozygous patient had onset of nephrotic syndrome at about 6 months, according to Table 1. Re-read Table 1 before encoding: the column alignment is ambiguous in text extraction.
Progression: rapid. Kidney failure at 22 months (A2438_22) and 3 years (A913_21).
Course: progressive and lifelong. No spontaneous or treatment-induced remission has been reported.
Critical periods: infancy. Early genetic diagnosis may spare children ineffective immunosuppression (general genetic-SRNS principle).
Stages: the general CKD trajectory (nephrotic syndrome → CKD → kidney failure) applies. There are no disease-specific stages.

9. Inheritance and population

Inheritance: autosomal recessive, HP:0000007 (ClinGen: "AR"; segregation consistent in families with parental DNA).
Penetrance and expressivity: unknown. Expressivity appears variable for extrarenal features, n = 2–3.
Anticipation and mosaicism: not applicable or not reported.
Founder effect: possible for p.Leu425Met in Turkey (2 of 3 probands); not formally tested.
Consanguinity: present in the homozygous family.
Epidemiology: ultra-rare, about 3–4 reported probands worldwide. No prevalence or incidence estimate exists. Use CASES_IN_LITERATURE / ULTRA_RARE rather than a numeric band. Context: in a 1,780-family SRNS cohort, about 30% had a monogenic cause among the 26 genes known at the time (PMID:29058690, citing PMID:25467131 per the paper's reference list; verify). AVIL was found in 3 of about 800+ resequenced SRNS individuals.
Geography and sex: Turkey (2), UK (1), probably Indonesia (1, unconfirmed). Sexes: 1 M, 2 F.
Carrier frequency: not established. Population allele counts are very low (e.g. ExAC A = 5/120,708 for c.1273C>A). gnomAD v4 was not consulted for this report.

10. Diagnostics

Laboratory: urine protein/creatinine ratio, serum albumin, lipids, creatinine/eGFR. These are generic nephrotic-syndrome tests; no AVIL-specific biomarker exists.
Biopsy: DMS on light microscopy; diffuse foot-process effacement on EM.
Genetic testing (key test): an SRNS multigene panel or exome sequencing. AVIL is listed in GeneReviews' syndromic genetic-SRNS gene table. Indonesian data argue for exome sequencing in early-onset or atypical SRNS: "Genetic testing should be integrated into routine SRNS evaluation, especially in atypical presentations or early-onset of the disease" (PMID:42420527). CMA, karyotype, FISH, mtDNA and repeat-expansion testing are not indicated for this gene. Because ClinGen rates the gene Limited, an AVIL finding should be interpreted cautiously and may be reported as a VUS-level gene.
Extrarenal work-up (justified by the reported features): ophthalmology (fundus/ERG, slit lamp), audiology, head circumference, developmental assessment.
Differential diagnosis:
Other DMS/early-onset SRNS genes: PLCE1 (closest phenocopy, same pathway), WT1 (Denys-Drash; genital and Wilms features), LAMB2 (Pierson; microcoria).
Congenital nephrotic syndrome genes: NPHS1, NPHS2.
Other syndromic SRNS: COQ2/COQ6/COQ8B (SNHL, neurologic; CoQ10-responsive, so important to exclude), Galloway-Mowat genes (WDR73, OSGEP/KEOPS; microcephaly plus SRNS, a key phenocopy of the A2438_22 picture), NUP107/NUP93.
Secondary/infectious congenital NS (CMV, syphilis, toxoplasmosis).
Screening: no newborn screening. Cascade carrier testing and prenatal or preimplantation testing are possible once familial variants are known.

11. Outcome and prognosis

Survival and mortality: no data. Kidney failure is expected in early childhood.
Morbidity: dialysis dependence; complications of nephrotic syndrome (edema, infection, thrombosis, dyslipidemia, growth failure); neurodevelopmental and sensory disability in syndromic cases.
Recurrence after transplant: not reported for AVIL. Genetic SRNS generally has a low risk of post-transplant recurrence (GeneReviews).
Prognostic factors: DMS histology and infantile onset predict rapid progression (inferred from the 2 cases and general DMS literature). No prognostic biomarkers exist.

12. Treatment

Intervention	NCIT suggestion	Evidence for AVIL	Notes
Kidney transplantation	NCIT:C15289 Organ Transplantation (used in draft; a more specific "Kidney Transplantation" NCIT term may exist, look up)	A913_21 was transplanted; outcome not reported	GeneReviews: "All genetic SRNS can be corrected with kidney transplantation."
Dialysis (PD/HD)	Look up NCIT dialysis term	Implied by ESRD at <3 years	Bridge to transplant
RAAS blockade (ACE inhibitor)	NCIT:C15986 Pharmacotherapy + therapeutic_agent (ACE inhibitor class)	A2438_22 received an ACE inhibitor (Table 1)	Antiproteinuric; no outcome data
Supportive care (albumin infusion, diuretics, nutrition, thromboprophylaxis, vaccination)	NCIT:C15747 Supportive Care	General	—
Calcineurin inhibitors / steroids	—	No AVIL data	Monogenic SRNS rarely responds. In the Indonesian cohort, 53.3% of all SRNS (not AVIL-specific) responded to cyclosporin, so do not attribute that figure to AVIL
Genetic counseling	NCIT:C15240 Genetic Counseling	—	AR, 25% recurrence risk

Pharmacogenomics, gene therapy, ASO/siRNA, cell therapy, clinical trials: none for AVIL. No ClinicalTrials.gov trials target AVIL-SRNS.
Speculative targets: the authors suggest the EGF–AVIL–PLCE1–ARP2/3 axis "may represent drug targets for SRNS". This is hypothesis only.

13. Prevention

Primary: none, beyond reproductive options.
Secondary: early molecular diagnosis in infantile SRNS avoids unnecessary immunosuppression.
Tertiary: standard CKD care (blood pressure, growth, bone mineral, anemia), plus infection and thrombosis prophylaxis in nephrotic syndrome.
Genetic counseling: carrier testing of relatives; prenatal or preimplantation genetic testing for known familial variants.
Vaccines and public-health measures: not applicable, beyond routine immunization of children with nephrotic syndrome or on dialysis.

14. Other species and natural disease

No naturally occurring AVIL-associated nephropathy is known in animals; no OMIA entry was found. Orthologs exist in mouse (Avil, MGI), rat (Avil, RGD 620301) and zebrafish (avil, ZFIN via Alliance). Leu425 is conserved back to Ciona intestinalis and Arg446 to C. elegans (Table 1). Not zoonotic.

15. Model organisms

Model	Finding	Fidelity to NPHS21
*Zebrafish avil* CRISPR knockdown** (Rao 2017; reported in ClinGen)	"our initial experiments did not show a larval edema phenotype"	Fails to recapitulate. Candidate for a `FAILS_TO_RECAPITULATE` link or a `HUMAN_MODEL_MISMATCH` discussion. The authors attribute earlier positive SRNS zebrafish models to unreliable morpholinos
*Mouse Avil* null / knock-in** (Hasegawa et al. 2007, J Neurosci; Avil-hPLAP knock-in)	Expression almost exclusively in peripheral sensory neurons. Null mice show shortened regenerative axon growth and reduced barrelette plasticity	No kidney phenotype reported. Glomerular phenotyping not described. Advillin-Cre lines are widely used sensory-neuron drivers; their expression also reaches autonomic neurons postnatally (eNeuro 2018)
Human immortalized podocytes (Saleem line) with siRNA/shRNA knockdown and rescue	Loss of stress fibers, PLCE1 mislocalization, loss of DAG, reduced migration; WT rescues, patient alleles do not	In vitro mechanism model; migration rate is a proxy readout. Mechanism node at CELLULAR scale, extrapolated upward to TISSUE
Recombinant protein assays	Bundling, binding and severing defects (§6)	MOLECULAR
Related biochemistry	George et al. 2020, Mol Biol Cell (PMID:32520642): conserved F-actin-bundling residues in villin-type headpiece domains, tested in advillin	Supports headpiece-dependent bundling; not disease-specific

Gaps. No podocyte-specific Avil conditional knockout. No patient iPSC-derived podocytes or kidney organoids. Whether there is real AVIL protein expression in the adult human glomerulus needs confirming; the Human Protein Atlas was not checked here.

Key gaps and curation recommendations

The single-publication evidence base (ClinGen Limited) should appear in the entry's description, and the gene_disease_validity LIMITED row should be kept.
Fetch the full text of PMID:42420527 to see whether a second AVIL proband (Indonesia) is described, with genotype and phenotype.
The syndromic features are n = 1 each and come from consanguineous families. Encode them as reported, without implying they are core features.
Encode the zebrafish null result as a negative model finding.
Possible duplicate entry. The worktree contains both Nephrotic_Syndrome_Type_21.yaml and AVIL-Related_Steroid-Resistant_Nephrotic_Syndrome.yaml. They appear to be the same disease (MONDO:0032826), and only one should be kept.
CURIEs marked (verify) above were not looked up in this session. Each must be resolved with runoak/OLS before binding.

Sources

Rao J, Ashraf S, et al. Advillin acts upstream of phospholipase C ε1 in steroid-resistant nephrotic syndrome. J Clin Invest 2017;127(12):4257–4269. PMID:29058690. PubMed · PMC5707164 · JCI figure 4
Heintze JM. AVIL mutations reduce podocyte migration rate in SRNS (research highlight). Nat Rev Nephrol 2018. PMID:29129927.
ClinGen Glomerulopathy GCEP. AVIL / nephrotic syndrome, type 21: Limited (2023-06-27; re-evaluated 2024-08-27). ClinGen report
GeneReviews. Genetic Steroid-Resistant Nephrotic Syndrome Overview (NBK573219; PMID:34436835). https://www.ncbi.nlm.nih.gov/books/NBK573219/
Fahlevi R, et al. Genetic mutation patterns in Indonesian children with primary SRNS. Pediatr Nephrol 2026. PMID:42420527.
George SP, et al. F-actin-bundling sites are conserved in proteins with villin-type headpiece domains. Mol Biol Cell 2020. PMID:32520642.
OMIM *613397 AVIL · ClinVar RCV000845156 (p.Arg446His) · GeneCards AVIL
Hasegawa H, et al. Analyzing somatosensory axon projections with the sensory neuron-specific Advillin gene. J Neurosci 2007. PMID not verified here; look it up before citing. Duke Scholars record
Advillin expression in neural-crest-derived neurons: eNeuro 2018, ENEURO.0077-18.2018; Advillin-Cre usage example: PMC5346175
RGD Avil · Alliance/ZFIN avil

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	8
On topic	5
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	33
Resolved	31
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	3
Terms named correctly	0
Terms named as a different term	1
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0000007 (1 mention) - the report calls it "ClinGen: "AR"; segregation consistent in families with parental DNA"; HP calls it Autosomal recessive inheritance

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

CL:0000653 (2 mentions) - the report calls it "Cell: podocyte"; CL calls it podocyte**, and lists "renal podocyte" among its other names
GO:0030027 (1 mention) - the report calls it "Subcellular: lamellipodium"; GO calls it lamellipodium**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: CCID.

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Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

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Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Nephrotic Syndrome Type 21 (NPHS21; AVIL-related steroid-resistant nephrotic syndrome): research report

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Ontology suggestions

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Key gaps and curation recommendations

Sources

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver