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Classifications

Harrison's Part

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Heterozygous germline variants were inherited in every family where parents were tested, from a parent without medulloblastoma. Penetrance for childhood medulloblastoma is low. The only estimate is a population-based projection from the four definite truncating carriers in the discovery cohorts and the gnomAD truncating-variant frequency; no carrier cohort has been followed prospectively.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (4 references)

CGGV:assertion_126a60ed-67a8-4d42-841e-cc88b1138fbc-2026-01-13T170000.000Z SUPPORT Other

ClinGen records autosomal dominant inheritance for this MONDO term.

PMID:31609649 SUPPORT Human Clinical

"analysis of two available parent-offspring trios (M20769 and MB13_03) demonstrated parental transmission in both affected patients"

Both trios in the defining series showed parental transmission of the germline variant.

PMID:38424437 SUPPORT Human Clinical

"At least one family member was tested in two of the six families, and in both cases the variant was inherited from a parent without personal or family history of MB."

The transmitting parents were unaffected, which supports incomplete penetrance.

+ 1 more reference

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Discussions and Knowledge Gaps

3

Is GPR161-related medulloblastoma predisposition a separate condition, or a gene within nevoid basal cell carcinoma (Gorlin) syndrome?

CONTROVERSY OPEN controversy_gpr161_gorlin_lump

Attached to

disease#

The sources disagree. ClinGen curates GPR161 against this MONDO term and split it from the other GPR161 phenotypes, and a screen of 27 Gorlin families without PTCH1 or SUFU variants found no GPR161 variant. The 2025 WHO genetic tumour syndrome classification instead lists GPR161 with PTCH1 and SUFU under nevoid basal cell carcinoma syndrome, and the 2024 AACR update describes a Gorlin-like phenotype in some carriers. That phenotype rests mainly on the index patient, whose basal cell carcinomas all arose in the radiation field of her medulloblastoma treatment. This entry follows MONDO and ClinGen and is curated separately from the PTCH1- and SUFU-related entries.

Show evidence (5 references)

CGGV:assertion_126a60ed-67a8-4d42-841e-cc88b1138fbc-2026-01-13T170000.000Z SUPPORT Other

"Therefore, the following disease entities have been split into multiple disease entities: GPR161-related medulloblastoma predisposition, Pituitary stalk interruption syndrome, Spina bifida."

ClinGen's lump/split decision for GPR161.

PMID:36961676 SUPPORT Human Clinical

"Our specific screen of GPR161 in our cohort of 27 PTCH1/SUFU pathogenic variant-negative patients with Gorlin syndrome found no pathogenic or likely pathogenic variants."

Against GPR161 as a Gorlin syndrome gene.

PMID:41210224 REFUTE Other

"Naevoid basal cell carcinoma syndrome (Gorlin syndrome) | PTCH1, SUFU, GPR161"

The WHO classification (beta version) lumps GPR161 into Gorlin syndrome, contradicting a separate entry.

+ 2 more references

What is the actual medulloblastoma risk for a GPR161 truncating-variant carrier, and does it justify any imaging surveillance?

KNOWLEDGE GAP OPEN gap_gpr161_penetrance_and_surveillance

Attached to

inheritance#Autosomal dominant inheritance treatments#Genetic Counseling and Symptom Education

The only risk figure is a projection from four truncating cases and gnomAD allele counts. No carrier cohort has been followed, and the guideline position against surveillance rests on that projection.

Show evidence (1 reference)

PMID:36961676 SUPPORT Computational

"We excluded the putative missense variant in GPR161 and the index case leaving only 4 definite loss-of-function variants amongst 1040 cases."

Shows how few cases the penetrance estimate rests on.

Do GPR161 carriers have any tumor risk beyond infant SHH medulloblastoma?

KNOWLEDGE GAP OPEN gap_gpr161_tumor_spectrum

Attached to

phenotypes#Infant SHH-Activated Medulloblastoma

Almost all reported carriers were children ascertained through medulloblastoma. The adult tumors reported (in the index patient, a meningioma, colorectal and gastric lesions and basal cell carcinomas within the radiation field; in her carrier father, colon adenocarcinoma) are single observations and are not curated as phenotypes here.

Show evidence (1 reference)

PMID:31609649 SUPPORT Human Clinical

"Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations."

The defining series names the gap.

⚙

Pathophysiology

6

Germline GPR161 Loss-of-Function

A heterozygous constitutional GPR161 variant, protein-truncating in most probands and a predicted damaging missense in one, removes one functional copy of a ciliary G protein-coupled receptor. GPR161 signals constitutively to raise cAMP and anchors type I protein kinase A regulatory subunits, and its PKA-binding site is required for it to keep the Hedgehog pathway repressed.

GPR161 hgnc:23694 ↓ DECREASED

Genetic context GPR161 hgnc:23694 variant_origin: GERMLINE allelic_hit_role: FIRST_HIT allelic_event: PATHOGENIC_VARIANT zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Constitutional heterozygous GPR161 variants, mostly frameshift or nonsense; one frameshift recurred in three unrelated probands.

G protein-coupled receptor activity GO:0004930 ↓ DECREASED protein kinase A regulatory subunit binding GO:0034237 ↓ DECREASED

Downstream

Somatic Loss of the Wild-Type GPR161 Allele Every cerebellar progenitor carries the first hit, so one somatic event at 1q completes biallelic loss.

Show evidence (7 references)

PMID:31609649 SUPPORT Human Clinical

"We identified heterozygous germline mutations in the G protein-coupled receptor 161 (GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years)."

Defines the constitutional heterozygous lesion.

PMID:31609649 SUPPORT Human Clinical

"Four patients were found to harbor GPR161 protein-truncating variants and one patient was a carrier of a predicted damaging missense variant (SJMB054)."

Allele spectrum of the probands found in the extension cohorts.

PMID:31609649 SUPPORT Human Clinical

"Two patients (MB11_06 and SJMB335) shared the same frameshift mutation as that of the index patient; kinship analysis demonstrated that all three patients were unrelated."

The recurrent frameshift in three unrelated probands.

+ 4 more references

Somatic Loss of the Wild-Type GPR161 Allele

The wild-type GPR161 allele is lost in the tumor in every carrier studied: in five of six by copy-neutral loss of heterozygosity of chromosome 1q and in one by a focal deletion of the whole gene. Among 226 SHH medulloblastomas, 1q copy-neutral loss of heterozygosity occurred only in GPR161 carriers.

cerebellar granule cell precursor CL:0002362

GPR161 hgnc:23694 ↓ DECREASED

Genetic context GPR161 hgnc:23694 variant_origin: SOMATIC allelic_hit_role: SECOND_HIT allelic_event: LOSS_OF_HETEROZYGOSITY allelic_event: DELETION functional_impact_category: LOSS_OF_FUNCTION

Somatic copy-neutral loss of heterozygosity of 1q, or less often a focal deletion spanning GPR161.

G protein-coupled receptor activity GO:0004930 ↓ DECREASED

cerebellum UBERON:0002037

Downstream

Biallelic GPR161 Loss in Cerebellar Granule Cell Precursors

Show evidence (3 references)

PMID:31609649 SUPPORT Human Clinical

"Analysis of 226 MBSHH tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation of GPR161 in affected MBSHH tumors."

Names 1q copy-neutral loss of heterozygosity as the second hit.

PMID:31609649 SUPPORT Human Clinical

"Remarkably, five of six patients with MB demonstrated an inactivation of GPR161 as a result of cnLOH of 1q and in one tumor a focal approximate 425-kb deletion spanned all exons of GPR161."

The two second-hit routes and their counts.

PMID:31609649 SUPPORT BACKGROUND Other

"GCs of the cerebellum are by far the most numerous neurons in the brain and MBSHH originates from their progenitors (GC progenitors [GCPs])."

Basis for placing the second hit in cerebellar granule cell precursors. The paper states the cell of origin of SHH medulloblastoma from earlier work; it did not show where the second hit occurred in carriers.

Biallelic GPR161 Loss in Cerebellar Granule Cell Precursors

Cells that have lost both GPR161 alleles lose the receptor's basal repressive signal to the Hedgehog pathway. Biallelic GPR161 inactivation was the only driver event shared by the six carrier tumors.

cerebellar granule cell precursor CL:0002362

GPR161 hgnc:23694 ∅ ABSENT

G protein-coupled receptor activity GO:0004930 ∅ ABSENT

Downstream

Derepression of Hedgehog Signaling

Show evidence (1 reference)

PMID:31609649 SUPPORT Human Clinical

"Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MBSHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events."

Biallelic loss in every carrier tumor, with no other shared driver.

Derepression of Hedgehog Signaling

Without GPR161, processing of GLI3 to its repressor form falls and Hedgehog target genes are expressed without ligand, before Purkinje cells begin secreting Sonic hedgehog. The lesion acts on the PKA-GLI3 repressor arm and is distinct from the PTCH1 and SUFU lesions of nevoid basal cell carcinoma syndrome.

cerebellar granule cell precursor CL:0002362

negative regulation of smoothened signaling pathway GO:0045879 ↓ DECREASED smoothened signaling pathway GO:0007224 ↑ INCREASED

Animal models

Gpr161 conditional knockout mouse (neural stem cell or granule progenitor) Mouse recapitulates Deleting Gpr161 in cerebellar lineages raises Hedgehog pathway output through loss of Gli3 repressor.

Downstream

Granule Cell Precursor Overproduction and Proliferation

Show evidence (2 references)

PMID:29386106 SUPPORT Model Organism

"Irrespective of Shh production in the cerebellum, Gpr161 deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors."

Conditional Gpr161 deletion in mouse cerebellar lineages derepresses the pathway through loss of Gli3 repressor, independent of ligand.

PMID:23332756 SUPPORT Model Organism

"Complete loss of Gpr161 in mouse causes midgestation lethality and increased Shh signaling in the neural tube, phenocopying Tulp3/IFT-A mutants."

Gpr161-null mouse embryos show increased Shh signaling in vivo.

Granule Cell Precursor Overproduction and Proliferation

In the mouse, Gpr161 loss in neural stem cells or granule cell progenitors increases the generation and proliferation of granule progenitors, and deletion earlier in embryogenesis gives more and more severe tumors. The embryonic window is consistent with the infant onset in carriers.

cerebellar granule cell precursor CL:0002362

cerebellar granule cell precursor proliferation GO:0021930 ↑ INCREASED

cerebellum UBERON:0002037

Downstream

SHH-Activated Medulloblastoma Initiation

Show evidence (2 references)

PMID:29386106 SUPPORT Model Organism

"Gpr161 restricts GC progenitor production by preventing premature and Shh-dependent pathway activity, highlighting the importance of basal pathway suppression in tumorigenesis."

Granule progenitor overproduction as the consequence of lost basal repression.

PMID:29386106 SUPPORT Model Organism

"Moreover, earlier deletion of Gpr161 during embryogenesis increased tumor incidence and severity."

Timing of loss during development sets tumor burden in the mouse.

SHH-Activated Medulloblastoma Initiation

GPR161-deficient granule progenitors give rise to SHH-activated medulloblastoma. No other somatic driver is shared across carrier tumors, which supports GPR161 loss as sufficient for initiation. Mouse tumors after Gpr161 loss are milder than after Ptch1 loss, consistent with weaker pathway induction.

cerebellum UBERON:0002037

Animal models

Gpr161 conditional knockout mouse (neural stem cell or granule progenitor) Mouse partially recapitulates The mice develop SHH-type medulloblastoma that groups with Smo-driven mouse tumors and human SHH medulloblastoma.

Downstream

Infant SHH-Activated Medulloblastoma

Show evidence (2 references)

PMID:31609649 SUPPORT Human Clinical

"Of note, analysis of somatic mutations in known and putative MB driver genes revealed biallelic inactivation of GPR161 as the sole shared event across the six patients, indicating that loss of GPR161 is sufficient for tumor growth"

Human tumor genomics supporting GPR161 loss as the initiating driver.

PMID:29386106 SUPPORT Model Organism

"The severity and extent of tumorigenesis is weaker than with respect to Ptch1 conditional knockout mice (Yang et al., 2008) because Shh pathway induction upon Gpr161 depletion is weaker than upon Smo activation (Mukhopadhyay et al., 2013)."

Weaker tumor phenotype of Gpr161 loss than of Ptch1 loss in the mouse.

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Pathograph

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

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Phenotypes

1

Infant SHH-Activated Medulloblastoma Neoplastic HP:0002885

Onset: INFANTILE

Show evidence (4 references)

PMID:31609649 SUPPORT Human Clinical

"GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MBSHH) subgroup and accounted for 5% of infant MBSHH cases in our cohorts."

Restriction to the SHH subgroup and contribution to infant SHH medulloblastoma.

PMID:31609649 SUPPORT Human Clinical

"Carriers of a protein-truncating germline mutation in GPR161 reported here developed MBSHH before the age of 3 years."

Upper bound of onset among truncating-variant carriers.

PMID:31609649 SUPPORT Human Clinical

"We assessed TP53 mutation status across all MBSHH and observed that all GPR161-associated MBSHH were TP53 wild type"

Places the tumors in the TP53-wildtype SHH category.

+ 1 more reference

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Genetic Associations

1

GPR161 (Germline tumor suppressor predisposition)

Gene: GPR161 hgnc:23694 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:31609649 SUPPORT Human Clinical

"Finally, germline GPR161 protein-truncating variants were significantly enriched in pediatric patients with MBSHH compared with the general population (one in 30 patients v one in 1,664 controls in gnomAD; P = 2×10−9, Fisher’s exact test)."

Case-control enrichment of truncating variants.

PMID:39184053 SUPPORT Human Clinical

"We identified P/LP variants in four of the six medulloblastoma genes: APC, ELP1, GPR161, and SUFU"

An independent survivor cohort includes a GPR161 carrier.

CGGV:assertion_126a60ed-67a8-4d42-841e-cc88b1138fbc-2026-01-13T170000.000Z SUPPORT Other

"Five variants (missense, in-frame indel, nonsense, frameshift) that have been reported in seven probands in two publications (PMIDs: 31609649, 39184053) are included in this curation."

ClinGen's count of the human genetic evidence.

💊

Medical Actions

1

Genetic Counseling and Symptom Education

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Carriers and their families are counselled about the low absolute medulloblastoma risk and taught the signs and symptoms of a posterior fossa tumor, with an annual CNS-focused physical examination. Routine brain MRI surveillance is not recommended; the 2024 AACR pediatric predisposition update allows a personalized imaging plan, for example for a carrier sibling of an affected child, after shared decision making.

Show evidence (4 references)

PMID:38573059 SUPPORT Other

"Since the absolute risk of MB development in germline GPR161 is currently considered low(32), surveillance with brain imaging may not be warranted."

Consensus guideline position against routine imaging surveillance.

PMID:38573059 SUPPORT Other

"Education regarding signs and symptoms; consider further screening based on family history and shared decision making with family"

The guideline's GPR161 surveillance recommendation.

PMID:38573059 SUPPORT Other

"At a minimum, it is helpful for the parents to understand the signs and symptoms of the associated tumors and for the child to get an annual, comprehensive and CNS-targeted physical exam."

Minimum follow-up for carriers of genes without formal recommendations, a group in which the guideline names GPR161.

+ 1 more reference

🔬

Diagnosis

2

Germline GPR161 genetic testing

Germline GPR161 testing is suggested for children with SHH-activated medulloblastoma, particularly those diagnosed in infancy. A heterozygous pathogenic GPR161 variant in constitutional DNA establishes the diagnosis.

germline GPR161 genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:33194646 SUPPORT Other

"Furthermore, we suggest that patients with MBSHH should be tested for germline ELP1 mutations, especially those presenting outside of infancy, and for germline GPR161 mutations, particularly those presenting in infancy."

Review recommendation on whom to test.

Tumor chromosome 1q copy-neutral loss of heterozygosity

Copy-neutral loss of heterozygosity of 1q in an SHH medulloblastoma was found only in germline GPR161 carriers in the defining series and was proposed as a tumor marker for selecting patients for germline testing. It has not been validated in an independent series.

tumor copy number and loss-of-heterozygosity analysis NCIT:C20826

Show evidence (1 reference)

PMID:31609649 SUPPORT Human Clinical

"This analysis revealed that 1q cnLOH is exclusively present in tumors with germline GPR161 mutations (GPR161MUT = five of six v GPR161WT = zero of 220; P = 8.8×10−8, Fisher’s exact test), which suggests that 1q cnLOH is a hallmark for GPR161 deficiency and a molecular marker for the..."

Specificity of the marker and the proposal to use it.

🐁

Animal Models

1

Gpr161 conditional knockout mouse (neural stem cell or granule progenitor)

Species

Mouse

Genotype

Gpr161 floxed exon 4, homozygous, with hGFAP-Cre, Nestin-Cre or Atoh1-Cre

Publication

PMID:29386106

Pathograph links

Derepression of Hedgehog Signaling recapitulates fidelity: moderate Deleting Gpr161 in cerebellar lineages raises Hedgehog pathway output through loss of Gli3 repressor.

Limitations: Both alleles are deleted in the whole Cre lineage, unlike a germline heterozygote with a clonal somatic second hit, so the model does not address penetrance.

Show evidence (1 reference)

PMID:29386106 SUPPORT Model Organism

"Irrespective of Shh production in the cerebellum, Gpr161 deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors."

Shows the derepression in the model.

SHH-Activated Medulloblastoma Initiation partially recapitulates fidelity: moderate The mice develop SHH-type medulloblastoma that groups with Smo-driven mouse tumors and human SHH medulloblastoma.

Limitations: Tumors are milder than after Ptch1 deletion, and they arise from lineage-wide biallelic deletion rather than a germline heterozygous state with somatic 1q loss of heterozygosity.

Show evidence (1 reference)

PMID:29386106 SUPPORT Model Organism

"Multiple lines of evidence, including RNA sequencing (RNA-seq) analysis and immunohistochemistry, group the Shh-MB tumors in Gpr161 conditional knockout mice with SmoM2-induced tumors in mice and human SHH-MB."

Tumor identity in the model.

{ }

Source YAML

click to show

name: GPR161-related medulloblastoma predisposition
creation_date: '2026-10-13T19:45:06Z'
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Pediatric Cancer
parents:
- hereditary neoplastic syndrome
disease_term:
  preferred_term: GPR161-related medulloblastoma predisposition
  term:
    id: MONDO:1010204
    label: GPR161-related medulloblastoma predisposition
synonyms: []
description: >-
  GPR161-related medulloblastoma predisposition is an autosomal dominant,
  low-penetrance childhood brain tumor predisposition caused by heterozygous
  germline loss-of-function variants, mostly truncating, in GPR161 (1q24.2).
  GPR161 encodes a cilium-localized orphan G protein-coupled receptor that
  keeps the Sonic hedgehog pathway basally repressed through cAMP and protein
  kinase A. The only established tumor is SHH-activated, TP53-wildtype
  medulloblastoma of infancy, with a median age at diagnosis of 1.5 years in
  the defining series. In the tumor the wild-type allele is lost, usually by
  somatic copy-neutral loss of heterozygosity of chromosome 1q, and no other
  SHH-pathway driver is shared across carrier tumors. Germline variants explain
  about 3 per cent of pediatric and 5 per cent of infant SHH medulloblastoma.
  Because truncating variants are common in the general population and are
  usually inherited from an unaffected parent, the childhood risk for a carrier
  has been estimated at about 1 in 1,600 to 1 in 2,500. Brain imaging
  surveillance is not recommended; families are counselled about the signs
  and symptoms of medulloblastoma. Whether carriers have any further tumor risk is
  unknown.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    Heterozygous germline variants were inherited in every family where
    parents were tested, from a parent without medulloblastoma. Penetrance for
    childhood medulloblastoma is low. The only estimate is a population-based
    projection from the four definite truncating carriers in the discovery
    cohorts and the gnomAD truncating-variant frequency; no carrier cohort has
    been followed prospectively.
  evidence:
  - reference: CGGV:assertion_126a60ed-67a8-4d42-841e-cc88b1138fbc-2026-01-13T170000.000Z
    reference_title: GPR161 / GPR161-related medulloblastoma predisposition (Strong)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GPR161 | HGNC:23694 | GPR161-related medulloblastoma predisposition | MONDO:1010204 | AD | Strong"
    explanation: >-
      ClinGen records autosomal dominant inheritance for this MONDO term.
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "analysis of two available parent-offspring trios (M20769 and MB13_03) demonstrated parental transmission in both affected patients"
    explanation: >-
      Both trios in the defining series showed parental transmission of the
      germline variant.
  - reference: PMID:38424437
    reference_title: The evolutionary impact of childhood cancer on the human gene pool.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At least one family member was tested in two of the six families, and in both cases the variant was inherited from a parent without personal or family history of MB."
    explanation: >-
      The transmitting parents were unaffected, which supports incomplete
      penetrance.
  - reference: PMID:36961676
    reference_title: Perspectives on the implications of carrying putative pathogenic variants in the medulloblastoma predisposition genes ELP1 and GPR161.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The projected risks are around 1 in 270-430 for ELP1 and 1 in 1600-2500 for GPR161."
    explanation: >-
      Projected childhood medulloblastoma risk for a GPR161 truncating-variant
      carrier, from population incidence and a case-versus-gnomAD odds ratio.
      It is a modelled estimate, not an observed carrier cohort.
pathophysiology:
- name: Germline GPR161 Loss-of-Function
  conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
  biological_scale: MOLECULAR
  description: >-
    A heterozygous constitutional GPR161 variant, protein-truncating in most
    probands and a predicted damaging missense in one, removes one functional
    copy of a ciliary G protein-coupled receptor. GPR161 signals constitutively
    to raise cAMP and anchors type I protein kinase A regulatory subunits, and
    its PKA-binding site is required for it to keep the Hedgehog pathway
    repressed.
  gene:
    preferred_term: GPR161
    modifier: DECREASED
    term:
      id: hgnc:23694
      label: GPR161
  genetic_context:
    gene:
      preferred_term: GPR161
      term:
        id: hgnc:23694
        label: GPR161
    variant_origin: GERMLINE
    allelic_hit_role: FIRST_HIT
    allelic_events:
    - PATHOGENIC_VARIANT
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Constitutional heterozygous GPR161 variants, mostly frameshift or
      nonsense; one frameshift recurred in three unrelated probands.
  molecular_functions:
  - preferred_term: G protein-coupled receptor activity
    modifier: DECREASED
    term:
      id: GO:0004930
      label: G protein-coupled receptor activity
  - preferred_term: protein kinase A regulatory subunit binding
    modifier: DECREASED
    term:
      id: GO:0034237
      label: protein kinase A regulatory subunit binding
  evidence:
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified heterozygous germline mutations in the G protein-coupled receptor 161 (GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years)."
    explanation: >-
      Defines the constitutional heterozygous lesion.
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients were found to harbor GPR161 protein-truncating variants and one patient was a carrier of a predicted damaging missense variant (SJMB054)."
    explanation: >-
      Allele spectrum of the probands found in the extension cohorts.
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients (MB11_06 and SJMB335) shared the same frameshift mutation as that of the index patient; kinship analysis demonstrated that all three patients were unrelated."
    explanation: >-
      The recurrent frameshift in three unrelated probands.
  - reference: CGGV:assertion_126a60ed-67a8-4d42-841e-cc88b1138fbc-2026-01-13T170000.000Z
    reference_title: GPR161 / GPR161-related medulloblastoma predisposition (Strong)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity is reported to be loss of function."
    explanation: >-
      ClinGen's statement of the disease mechanism.
  - reference: PMID:23332756
    reference_title: The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Constitutive Gpr161 activity increases cAMP levels and represses Shh signaling by determining the processing of Gli3 to its repressor form."
    explanation: >-
      Basis for the G protein-coupled receptor activity binding. Graded
      IN_VITRO because the cAMP measurements in this paper are cell-based.
  - reference: PMID:27357676
    reference_title: Gpr161 anchoring of PKA consolidates GPCR and cAMP signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that Gpr161 functions as a selective high-affinity AKAP for type I PKA regulatory subunits (RI)."
    explanation: >-
      Basis for the protein kinase A regulatory subunit binding.
  - reference: PMID:38326651
    reference_title: GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By contrast, a protein kinase A-binding site in the GPR161 C terminus is critical in suppressing GLI2 ciliary accumulation."
    explanation: >-
      The PKA-binding site, rather than Gs coupling, is what GPR161 needs to
      suppress ciliary GLI2 in this study.
  downstream:
  - target: Somatic Loss of the Wild-Type GPR161 Allele
    causal_link_type: DIRECT
    description: >-
      Every cerebellar progenitor carries the first hit, so one somatic event
      at 1q completes biallelic loss.
- name: Somatic Loss of the Wild-Type GPR161 Allele
  conforms_to: "germline_two_hit_tumor_predisposition#Somatic Second-Hit Inactivation of the Wild-Type Allele"
  biological_scale: MOLECULAR
  description: >-
    The wild-type GPR161 allele is lost in the tumor in every carrier studied:
    in five of six by copy-neutral loss of heterozygosity of chromosome 1q and
    in one by a focal deletion of the whole gene. Among 226 SHH
    medulloblastomas, 1q copy-neutral loss of heterozygosity occurred only in
    GPR161 carriers.
  gene:
    preferred_term: GPR161
    modifier: DECREASED
    term:
      id: hgnc:23694
      label: GPR161
  genetic_context:
    gene:
      preferred_term: GPR161
      term:
        id: hgnc:23694
        label: GPR161
    variant_origin: SOMATIC
    allelic_hit_role: SECOND_HIT
    allelic_events:
    - LOSS_OF_HETEROZYGOSITY
    - DELETION
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Somatic copy-neutral loss of heterozygosity of 1q, or less often a focal
      deletion spanning GPR161.
  molecular_functions:
  - preferred_term: G protein-coupled receptor activity
    modifier: DECREASED
    term:
      id: GO:0004930
      label: G protein-coupled receptor activity
  cell_types:
  - preferred_term: cerebellar granule cell precursor
    term:
      id: CL:0002362
      label: cerebellar granule cell precursor
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of 226 MBSHH tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation of GPR161 in affected MBSHH tumors."
    explanation: >-
      Names 1q copy-neutral loss of heterozygosity as the second hit.
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkably, five of six patients with MB demonstrated an inactivation of GPR161 as a result of cnLOH of 1q and in one tumor a focal approximate 425-kb deletion spanned all exons of GPR161."
    explanation: >-
      The two second-hit routes and their counts.
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "GCs of the cerebellum are by far the most numerous neurons in the brain and MBSHH originates from their progenitors (GC progenitors [GCPs])."
    explanation: >-
      Basis for placing the second hit in cerebellar granule cell precursors.
      The paper states the cell of origin of SHH medulloblastoma from earlier
      work; it did not show where the second hit occurred in carriers.
  downstream:
  - target: Biallelic GPR161 Loss in Cerebellar Granule Cell Precursors
    causal_link_type: DIRECT
- name: Biallelic GPR161 Loss in Cerebellar Granule Cell Precursors
  conforms_to: "germline_two_hit_tumor_predisposition#Biallelic Tumor Suppressor Inactivation in a Susceptible Cell"
  biological_scale: CELLULAR
  description: >-
    Cells that have lost both GPR161 alleles lose the receptor's basal
    repressive signal to the Hedgehog pathway. Biallelic GPR161 inactivation
    was the only driver event shared by the six carrier tumors.
  gene:
    preferred_term: GPR161
    modifier: ABSENT
    term:
      id: hgnc:23694
      label: GPR161
  molecular_functions:
  - preferred_term: G protein-coupled receptor activity
    modifier: ABSENT
    term:
      id: GO:0004930
      label: G protein-coupled receptor activity
  cell_types:
  - preferred_term: cerebellar granule cell precursor
    term:
      id: CL:0002362
      label: cerebellar granule cell precursor
  evidence:
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MBSHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events."
    explanation: >-
      Biallelic loss in every carrier tumor, with no other shared driver.
  downstream:
  - target: Derepression of Hedgehog Signaling
    causal_link_type: DIRECT
- name: Derepression of Hedgehog Signaling
  conforms_to: "hedgehog_pathway_activation#Loss of Hedgehog Pathway Negative Regulation"
  biological_scale: CELLULAR
  description: >-
    Without GPR161, processing of GLI3 to its repressor form falls and
    Hedgehog target genes are expressed without ligand, before Purkinje cells
    begin secreting Sonic hedgehog. The lesion acts on the PKA-GLI3 repressor
    arm and is distinct from the PTCH1 and SUFU lesions of nevoid basal cell
    carcinoma syndrome.
  biological_processes:
  - preferred_term: negative regulation of smoothened signaling pathway
    modifier: DECREASED
    term:
      id: GO:0045879
      label: negative regulation of smoothened signaling pathway
  - preferred_term: smoothened signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  cell_types:
  - preferred_term: cerebellar granule cell precursor
    term:
      id: CL:0002362
      label: cerebellar granule cell precursor
  evidence:
  - reference: PMID:29386106
    reference_title: Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Irrespective of Shh production in the cerebellum, Gpr161 deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors."
    explanation: >-
      Conditional Gpr161 deletion in mouse cerebellar lineages derepresses the
      pathway through loss of Gli3 repressor, independent of ligand.
  - reference: PMID:23332756
    reference_title: The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Complete loss of Gpr161 in mouse causes midgestation lethality and increased Shh signaling in the neural tube, phenocopying Tulp3/IFT-A mutants."
    explanation: >-
      Gpr161-null mouse embryos show increased Shh signaling in vivo.
  downstream:
  - target: Granule Cell Precursor Overproduction and Proliferation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29386106
      reference_title: Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Irrespective of Shh production in the cerebellum, Gpr161 deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors."
      explanation: >-
        States the step from pathway derepression to granule progenitor
        overproduction.
- name: Granule Cell Precursor Overproduction and Proliferation
  conforms_to: "hedgehog_pathway_activation#Hedgehog-Driven Proliferation and Tumorigenesis"
  biological_scale: CELLULAR
  description: >-
    In the mouse, Gpr161 loss in neural stem cells or granule cell progenitors
    increases the generation and proliferation of granule progenitors, and
    deletion earlier in embryogenesis gives more and more severe tumors. The
    embryonic window is consistent with the infant onset in carriers.
  biological_processes:
  - preferred_term: cerebellar granule cell precursor proliferation
    modifier: INCREASED
    term:
      id: GO:0021930
      label: cerebellar granule cell precursor proliferation
  cell_types:
  - preferred_term: cerebellar granule cell precursor
    term:
      id: CL:0002362
      label: cerebellar granule cell precursor
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:29386106
    reference_title: Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Gpr161 restricts GC progenitor production by preventing premature and Shh-dependent pathway activity, highlighting the importance of basal pathway suppression in tumorigenesis."
    explanation: >-
      Granule progenitor overproduction as the consequence of lost basal
      repression.
  - reference: PMID:29386106
    reference_title: Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, earlier deletion of Gpr161 during embryogenesis increased tumor incidence and severity."
    explanation: >-
      Timing of loss during development sets tumor burden in the mouse.
  downstream:
  - target: SHH-Activated Medulloblastoma Initiation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29386106
      reference_title: Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, by deleting Gpr161 in mouse neural stem cells or GC progenitors, we establish Gpr161 as a tumor suppressor in Shh subtype medulloblastoma."
      explanation: >-
        Deletion in granule progenitors is sufficient for SHH-type
        medulloblastoma in the mouse.
- name: SHH-Activated Medulloblastoma Initiation
  conforms_to: "germline_two_hit_tumor_predisposition#Clonal Expansion and Tumor Initiation"
  biological_scale: TISSUE
  description: >-
    GPR161-deficient granule progenitors give rise to SHH-activated
    medulloblastoma. No other somatic driver is shared across carrier tumors,
    which supports GPR161 loss as sufficient for initiation. Mouse tumors after
    Gpr161 loss are milder than after Ptch1 loss, consistent with weaker
    pathway induction.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, analysis of somatic mutations in known and putative MB driver genes revealed biallelic inactivation of GPR161 as the sole shared event across the six patients, indicating that loss of GPR161 is sufficient for tumor growth"
    explanation: >-
      Human tumor genomics supporting GPR161 loss as the initiating driver.
  - reference: PMID:29386106
    reference_title: Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The severity and extent of tumorigenesis is weaker than with respect to Ptch1 conditional knockout mice (Yang et al., 2008) because Shh pathway induction upon Gpr161 depletion is weaker than upon Smo activation (Mukhopadhyay et al., 2013)."
    explanation: >-
      Weaker tumor phenotype of Gpr161 loss than of Ptch1 loss in the mouse.
  downstream:
  - target: Infant SHH-Activated Medulloblastoma
    causal_link_type: DIRECT
phenotypes:
- category: Neoplastic
  name: Infant SHH-Activated Medulloblastoma
  description: >-
    SHH-activated, TP53-wildtype medulloblastoma diagnosed in infancy or early
    childhood: median 1.5 years in the six carriers of the defining series,
    with every truncating-variant carrier diagnosed before 3 years. Five of
    the six tumors fell in the SHH-beta infant subtype, though that enrichment
    was not significant. A further carrier with a nonsense variant and SHH
    medulloblastoma was found by germline exome sequencing of a pediatric brain
    tumor cohort.
  phenotype_term:
    preferred_term: SHH-activated medulloblastoma
    term:
      id: HP:0002885
      label: Medulloblastoma
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MBSHH) subgroup and accounted for 5% of infant MBSHH cases in our cohorts."
    explanation: >-
      Restriction to the SHH subgroup and contribution to infant SHH
      medulloblastoma.
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Carriers of a protein-truncating germline mutation in GPR161 reported here developed MBSHH before the age of 3 years."
    explanation: >-
      Upper bound of onset among truncating-variant carriers.
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We assessed TP53 mutation status across all MBSHH and observed that all GPR161-associated MBSHH were TP53 wild type"
    explanation: >-
      Places the tumors in the TP53-wildtype SHH category.
  - reference: PMID:39036440
    reference_title: Germline susceptibility from broad genomic profiling of pediatric brain cancers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This was demonstrated by the discovery of a GPR161 (NM_001375883.1) p.Tyr344Ter germline alteration in a patient with medulloblastoma."
    explanation: >-
      An independent carrier with medulloblastoma; the paper's case table
      gives age 1.5 years and SHH subgroup.
genetic:
- name: GPR161
  association: Germline tumor suppressor predisposition
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: GPR161
    term:
      id: hgnc:23694
      label: GPR161
  gene_disease_validity:
  - validity_classification: STRONG
    classified_by: CLINGEN
    external_id: CGGV:assertion_126a60ed-67a8-4d42-841e-cc88b1138fbc-2026-01-13T170000.000Z
    evidence:
    - reference: CGGV:assertion_126a60ed-67a8-4d42-841e-cc88b1138fbc-2026-01-13T170000.000Z
      reference_title: GPR161 / GPR161-related medulloblastoma predisposition (Strong)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "GPR161 | HGNC:23694 | GPR161-related medulloblastoma predisposition | MONDO:1010204 | AD | Strong"
      explanation: >-
        ClinGen gene-disease validity row for this MONDO term.
  case_fractions:
  - population: pediatric SHH-activated medulloblastoma (under 18 years), international cohorts
    case_fraction_percent: 3.4
    cohort_size: 178
    evidence:
    - reference: PMID:31609649
      reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall prevalence of germline GPR161 mutations among pediatric (age < 18 years) and infant (age < 4 years) patients with MBSHH was 3.4% (six of 178) and 5.5% (five of 91), respectively"
      explanation: >-
        Pediatric fraction.
  - population: infant SHH-activated medulloblastoma (under 4 years), international cohorts
    case_fraction_percent: 5.5
    cohort_size: 91
    evidence:
    - reference: PMID:31609649
      reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall prevalence of germline GPR161 mutations among pediatric (age < 18 years) and infant (age < 4 years) patients with MBSHH was 3.4% (six of 178) and 5.5% (five of 91), respectively"
      explanation: >-
        Infant fraction.
  notes: >-
    ClinGen classifies GPR161 for this MONDO term as Strong, autosomal
    dominant (2026-01-13), counting seven probands across two publications.
  evidence:
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, germline GPR161 protein-truncating variants were significantly enriched in pediatric patients with MBSHH compared with the general population (one in 30 patients v one in 1,664 controls in gnomAD; P = 2×10−9, Fisher’s exact test)."
    explanation: >-
      Case-control enrichment of truncating variants.
  - reference: PMID:39184053
    reference_title: Frequency of pathogenic germline variants in pediatric medulloblastoma survivors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified P/LP variants in four of the six medulloblastoma genes: APC, ELP1, GPR161, and SUFU"
    explanation: >-
      An independent survivor cohort includes a GPR161 carrier.
  - reference: CGGV:assertion_126a60ed-67a8-4d42-841e-cc88b1138fbc-2026-01-13T170000.000Z
    reference_title: GPR161 / GPR161-related medulloblastoma predisposition (Strong)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Five variants (missense, in-frame indel, nonsense, frameshift) that have been reported in seven probands in two publications (PMIDs: 31609649, 39184053) are included in this curation."
    explanation: >-
      ClinGen's count of the human genetic evidence.
treatments:
- name: Genetic Counseling and Symptom Education
  description: >-
    Carriers and their families are counselled about the low absolute
    medulloblastoma risk and taught the signs and symptoms of a posterior
    fossa tumor, with an annual CNS-focused physical examination. Routine
    brain MRI surveillance is not recommended; the 2024 AACR pediatric
    predisposition update allows a personalized imaging plan, for example for
    a carrier sibling of an affected child, after shared decision making.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38573059
    reference_title: Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Since the absolute risk of MB development in germline GPR161 is currently considered low(32), surveillance with brain imaging may not be warranted."
    explanation: >-
      Consensus guideline position against routine imaging surveillance.
  - reference: PMID:38573059
    reference_title: Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Education regarding signs and symptoms; consider further screening based on family history and shared decision making with family"
    explanation: >-
      The guideline's GPR161 surveillance recommendation.
  - reference: PMID:38573059
    reference_title: Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At a minimum, it is helpful for the parents to understand the signs and symptoms of the associated tumors and for the child to get an annual, comprehensive and CNS-targeted physical exam."
    explanation: >-
      Minimum follow-up for carriers of genes without formal recommendations,
      a group in which the guideline names GPR161.
  - reference: PMID:36961676
    reference_title: Perspectives on the implications of carrying putative pathogenic variants in the medulloblastoma predisposition genes ELP1 and GPR161.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Radiological screening for medulloblastoma appears not to be justified in incidentally identified cases but the risks for siblings of medulloblastoma cases who are heterozygotes may still justify closer monitoring."
    explanation: >-
      The same position, derived from the projected absolute risk.
diagnosis:
- name: Germline GPR161 genetic testing
  diagnosis_term:
    preferred_term: germline GPR161 genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Germline GPR161 testing is suggested for children with SHH-activated
    medulloblastoma, particularly those diagnosed in infancy. A heterozygous
    pathogenic GPR161 variant in constitutional DNA establishes the diagnosis.
  evidence:
  - reference: PMID:33194646
    reference_title: Cancer Predisposition Syndromes and Medulloblastoma in the Molecular Era.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Furthermore, we suggest that patients with MBSHH should be tested for germline ELP1 mutations, especially those presenting outside of infancy, and for germline GPR161 mutations, particularly those presenting in infancy."
    explanation: >-
      Review recommendation on whom to test.
- name: Tumor chromosome 1q copy-neutral loss of heterozygosity
  diagnosis_term:
    preferred_term: tumor copy number and loss-of-heterozygosity analysis
    term:
      id: NCIT:C20826
      label: Molecular Diagnosis
  description: >-
    Copy-neutral loss of heterozygosity of 1q in an SHH medulloblastoma was
    found only in germline GPR161 carriers in the defining series and was
    proposed as a tumor marker for selecting patients for germline testing.
    It has not been validated in an independent series.
  evidence:
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This analysis revealed that 1q cnLOH is exclusively present in tumors with germline GPR161 mutations (GPR161MUT = five of six v GPR161WT = zero of 220; P = 8.8×10−8, Fisher’s exact test), which suggests that 1q cnLOH is a hallmark for GPR161 deficiency and a molecular marker for the identification of patients with GPR161 mutations."
    explanation: >-
      Specificity of the marker and the proposal to use it.
animal_models:
- name: Gpr161 conditional knockout mouse (neural stem cell or granule progenitor)
  species: Mouse
  genotype: Gpr161 floxed exon 4, homozygous, with hGFAP-Cre, Nestin-Cre or Atoh1-Cre
  publication: PMID:29386106
  modeled_mechanisms:
  - target: Derepression of Hedgehog Signaling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Deleting Gpr161 in cerebellar lineages raises Hedgehog pathway output
      through loss of Gli3 repressor.
    limitations: >-
      Both alleles are deleted in the whole Cre lineage, unlike a germline
      heterozygote with a clonal somatic second hit, so the model does not
      address penetrance.
    evidence:
    - reference: PMID:29386106
      reference_title: Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Irrespective of Shh production in the cerebellum, Gpr161 deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors."
      explanation: >-
        Shows the derepression in the model.
  - target: SHH-Activated Medulloblastoma Initiation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The mice develop SHH-type medulloblastoma that groups with Smo-driven
      mouse tumors and human SHH medulloblastoma.
    limitations: >-
      Tumors are milder than after Ptch1 deletion, and they arise from
      lineage-wide biallelic deletion rather than a germline heterozygous
      state with somatic 1q loss of heterozygosity.
    evidence:
    - reference: PMID:29386106
      reference_title: Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Multiple lines of evidence, including RNA sequencing (RNA-seq) analysis and immunohistochemistry, group the Shh-MB tumors in Gpr161 conditional knockout mice with SmoM2-induced tumors in mice and human SHH-MB."
      explanation: >-
        Tumor identity in the model.
discussions:
- discussion_id: controversy_gpr161_gorlin_lump
  prompt: >-
    Is GPR161-related medulloblastoma predisposition a separate condition, or a
    gene within nevoid basal cell carcinoma (Gorlin) syndrome?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - disease#
  rationale: >-
    The sources disagree. ClinGen curates GPR161 against this MONDO term and
    split it from the other GPR161 phenotypes, and a screen of 27 Gorlin
    families without PTCH1 or SUFU variants found no GPR161 variant. The 2025
    WHO genetic tumour syndrome classification instead lists GPR161 with PTCH1
    and SUFU under nevoid basal cell carcinoma syndrome, and the 2024 AACR
    update describes a Gorlin-like phenotype in some carriers. That phenotype
    rests mainly on the index patient, whose basal cell carcinomas all arose
    in the radiation field of her medulloblastoma treatment. This entry follows
    MONDO and ClinGen and is curated separately from the PTCH1- and
    SUFU-related entries.
  evidence:
  - reference: CGGV:assertion_126a60ed-67a8-4d42-841e-cc88b1138fbc-2026-01-13T170000.000Z
    reference_title: GPR161 / GPR161-related medulloblastoma predisposition (Strong)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Therefore, the following disease entities have been split into multiple disease entities: GPR161-related medulloblastoma predisposition, Pituitary stalk interruption syndrome, Spina bifida."
    explanation: >-
      ClinGen's lump/split decision for GPR161.
  - reference: PMID:36961676
    reference_title: Perspectives on the implications of carrying putative pathogenic variants in the medulloblastoma predisposition genes ELP1 and GPR161.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our specific screen of GPR161 in our cohort of 27 PTCH1/SUFU pathogenic variant-negative patients with Gorlin syndrome found no pathogenic or likely pathogenic variants."
    explanation: >-
      Against GPR161 as a Gorlin syndrome gene.
  - reference: PMID:41210224
    reference_title: Towards a WHO classification of genetic tumour syndromes.
    supports: REFUTE
    evidence_source: OTHER
    snippet: "Naevoid basal cell carcinoma syndrome (Gorlin syndrome) | PTCH1, SUFU, GPR161"
    explanation: >-
      The WHO classification (beta version) lumps GPR161 into Gorlin syndrome,
      contradicting a separate entry.
  - reference: PMID:38573059
    reference_title: Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors.
    supports: REFUTE
    evidence_source: OTHER
    snippet: "These patients can have an overlapping NBCCS-like phenotype (i.e. develop other associated tumors including BCC and meningioma in probands and family members and Gorlin syndrome-like stigmata)."
    explanation: >-
      Describes a Gorlin-like phenotype in some carriers.
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 16 years, the patient developed her first basal-cell carcinoma (BCC) and has subsequently gone on to develop 10 more BCCs, all within the radiation field and all amenable to surgical removal."
    explanation: >-
      The index patient's basal cell carcinomas were confined to the radiation
      field, which leaves radiation as an explanation for them.
- discussion_id: gap_gpr161_penetrance_and_surveillance
  prompt: >-
    What is the actual medulloblastoma risk for a GPR161 truncating-variant
    carrier, and does it justify any imaging surveillance?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - inheritance#Autosomal dominant inheritance
  - treatments#Genetic Counseling and Symptom Education
  rationale: >-
    The only risk figure is a projection from four truncating cases and gnomAD
    allele counts. No carrier cohort has been followed, and the guideline
    position against surveillance rests on that projection.
  evidence:
  - reference: PMID:36961676
    reference_title: Perspectives on the implications of carrying putative pathogenic variants in the medulloblastoma predisposition genes ELP1 and GPR161.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We excluded the putative missense variant in GPR161 and the index case leaving only 4 definite loss-of-function variants amongst 1040 cases."
    explanation: >-
      Shows how few cases the penetrance estimate rests on.
- discussion_id: gap_gpr161_tumor_spectrum
  prompt: >-
    Do GPR161 carriers have any tumor risk beyond infant SHH medulloblastoma?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Infant SHH-Activated Medulloblastoma
  rationale: >-
    Almost all reported carriers were children ascertained through
    medulloblastoma. The adult tumors reported (in the index patient, a
    meningioma, colorectal and gastric lesions and basal cell carcinomas
    within the radiation field; in her carrier father, colon adenocarcinoma)
    are single observations and are not curated as phenotypes here.
  evidence:
  - reference: PMID:31609649
    reference_title: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations."
    explanation: >-
      The defining series names the gap.
notes: >-
  Curated as a germline predisposition entry separate from the tumor it
  predisposes to (Medulloblastoma_SHH_Activated), following design decision
  3a, and separate from the PTCH1- and SUFU-related nevoid basal cell
  carcinoma syndrome entries; the competing WHO lump into Gorlin syndrome is
  recorded as a controversy discussion. ClinGen split GPR161 medulloblastoma
  predisposition from pituitary stalk interruption syndrome (a homozygous
  GPR161 missense variant in one consanguineous family) and from spina bifida
  (rare heterozygous variants proposed as risk factors); neither is curated
  here.
  No GeneReviews chapter names this condition (just check-genereviews).

📚

References & Deep Research

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: GPR161-related_Medulloblastoma_Predisposition · 2026-10-13T23:57:13Z · View source

New entry for GPR161-related medulloblastoma predisposition (MONDO:1010204), curated as a germline predisposition separate from Medulloblastoma_SHH_Activated and from the PTCH1- and SUFU-related nevoid basal cell carcinoma syndrome entries. Deep research. A falcon (Edison) report was requested and its provider task was created (Edison trajectory ee86eb54-9615-4866-ad21-1b41e1f12838), but the Edison API returned 503 while the client polled it, and 19 attempts to rehydrate that trajectory over about 90 minutes failed with 'Failed to authenticate' while the API root returned 503. Falcon was not restarted. At the orchestrator's direction exactly one claude_code report was run instead and is the committed report (research/GPR161-related_Medulloblastoma_Predisposition-deep-research-claude_code.md). The falcon trajectory can be recovered later with just rehydrate-edison-trajectory ee86eb54-9615-4866-ad21-1b41e1f12838. The claude_code report was built from web-search snippets and was used as a lead only. Its one failed quote (PMC7658916, i.e. PMID:33194646) differs from the source only in formatting. Its carrier-frequency figure (1 in 42,000 to 1 in 125,000) is the per-variant frequency in Begemann 2020, not the overall truncating-variant frequency, so it was not used. Its statements that penetrance, ClinGen validity and surveillance guidance were unknown were superseded by the projected risk in PMID:36961676, the ClinGen Strong assertion, and the 2024 AACR update (PMID:38573059). just preflight-dr exited 2 because the local mondo.db is absent. Sources. Begemann et al. 2020 (PMID:31609649) is the defining series and supplies the allele spectrum, second-hit route, onset, subgroup and case fractions. The ClinGen gene-disease validity assertion for this MONDO term (Strong, AD, 2026-01-13) was cached from the current ClinGen download; that download does not match the sha256 pinned in data/clingen/MANIFEST.yaml, and the manifest was not repinned. Mechanism nodes rest on mouse conditional-knockout data (PMID:29386106) and on cell-based work (PMID:23332756, PMID:27357676, PMID:38326651). Management follows the AACR 2024 update. Lump/split: ClinGen split GPR161 medulloblastoma predisposition from pituitary stalk interruption syndrome and spina bifida, and neither is curated here. The 2025 WHO genetic tumour syndrome classification lists GPR161 under nevoid basal cell carcinoma syndrome; that is recorded as a CONTROVERSY discussion and not adopted. Gaps. Penetrance is a modelled projection from four truncating cases. The tumor spectrum beyond infant SHH medulloblastoma is unknown. The adult tumors in the index pedigree are not curated as phenotypes. No outcome or treatment-response data specific to carriers were found. Validation: just validate, validate-terms, count-verified-snippets (48/48), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-genereviews (NO_CHAPTER), list-gene-term-mismatches, check-block-scalar-comments, check-gene-validity, the gene-activity grounding guard, the ungated snippet/title/grading/retired-prose/environmental/coarse-phenotype/reference-title/folded-hyphen gates, and just validate-disorders (48 snippets, 48 titles, 0 issues) all passed.

Claude Code ▸

GPR161-related medulloblastoma predisposition: research report

claude-haiku-5-5, claude-sonnet-5-5 9 citations 2026-10-13T23:55:57.885568

GPR161-related medulloblastoma predisposition: research report

Evidence base and its limits. This report rests on web-search abstract snippets and secondary summaries. The PMC full text was blocked by a reCAPTCHA page, so I did not read the primary paper's full text. I did not extract variant-level details (cDNA/protein changes, de novo versus inherited, ClinVar IDs) or the functional-assay results. I found no post-2021 case reports or cohorts. Per your attribution rules, items marked [gap] have no source in hand. Items marked [inference] are my reasoning beyond the sources. Every PMID or identifier I could not confirm is marked unverified.

Source classes - Primary literature: Begemann et al., J Clin Oncol 2020, PMID:31609649 (PubMed, PMC6943973). - Commentary: Cancer Discovery 9(12):1645. I saw only its title. - Reviews: PMC7658916 and PMC11341988, as quoted in search snippets. - Gene-panel curation: Genomics England PanelApp panel 259. - Model-organism papers: Mukhopadhyay 2013, Shimada 2018, and an eLife knock-in study, seen through search summaries only.

1. Disease information

Entity. GPR161-related medulloblastoma predisposition is a germline, heterozygous tumor-predisposition syndrome. It is defined by infant-onset SHH-subgroup medulloblastoma.
Identifiers. MONDO:1010204 comes from your template and I did not verify it. OMIM, Orphanet, ICD, and MeSH were not checked [gap]. Medulloblastoma itself is OMIM #155255, and my search surfaced that entry.
Synonyms. "Germline GPR161 mutations predispose to pediatric medulloblastoma" is the paper's title phrase. Other names [gap].
Data source. The data come from patient cohorts in one study: families plus 1,044 medulloblastoma cases from international cohorts. They are not EHR-derived.
Lump/split, germline versus somatic (design decisions §3a). Keep this germline syndrome separate from the somatic SHH-medulloblastoma entry. The reported tumor spectrum is a single tumor type.
Authors' own caveat. The authors wrote that "Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations." Whether this is a syndrome or a single-tumor susceptibility is open.

2. Etiology

Cause. Heterozygous germline GPR161 loss-of-function variants, followed by a somatic loss of the wild-type allele.
Begemann 2020 (PMID:31609649, human clinical): "We identified heterozygous germline mutations in the G protein-coupled receptor 161 (GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years)."
The same abstract: "Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MB_SHH_ tumors… no additional somatic driver events."
Genetic risk modifiers. None known [gap].
Environmental risk and protective factors. None identified [gap]. Gene-environment interactions [gap].
Protective factors. None identified [gap].

3. Phenotypes

All figures come from the single index study (six patients), which I read only in abstract form.

Phenotype	HPO (verify before binding)	Frequency and notes
Medulloblastoma, SHH subgroup	HP:0002885 Medulloblastoma	All six patients. Median onset 1.5 years. The OMIM summary says the index case was a girl with SHH medulloblastoma at 12 months.
Other tumors	–	None reported [gap].
Neural tube defects	–	Not reported in carriers [gap]. A bioRxiv preprint cites GPR161 variants in spina bifida patients (Kim et al. 2019, secondhand).

Quality of life. [gap]
Penetrance and exact frequencies. [gap]. Do not infer them from a six-patient ascertainment series.
HPO term IDs. These are from memory, so verify each by lookup before binding.

4. Genetic and molecular information

Gene. GPR161, G protein-coupled receptor 161, on chromosome 1q24.
In this repo the HGNC CURIE is lowercase hgnc:. I did not look up the number, so no hgnc: ID is given here.
The chromosome position is from memory.
Variants. Per the abstract, heterozygous, in six patients. The variant list is not read [gap]. Pull it from the paper's tables and from ClinVar.
ClinGen validity. [gap]. Check for a CGGV record with just clingen-list.
PanelApp lists GPR161 as Green (high evidence) for "Childhood solid tumours cancer susceptibility" (panel 259).
A gene-panel rating is not a ClinGen assertion, so do not record it as classified_by: CLINGEN.
Allele frequency. Search snippets quote the paper: "the carrier frequency is approximately 1 in 42,000 to 1 in 125,000 individuals". The gnomAD source for this was not checked.
Second hit. Begemann 2020: "Analysis of 226 MB_SHH_ tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation."
This is classic two-hit biology.
Copy-neutral LOH on 1q fits the locus.
Functional consequence. Loss of function is the working model [inference from LOH plus gene biology]. The paper's functional assays [gap].
Epigenetic, chromosomal, and modifier-gene information. [gap]

5. Environmental information

None reported [gap]. No infectious agents are relevant.

6. Mechanism

Causal chain (the demonstrated links are the human genetic steps; most of the mechanism is from mouse work, and I only saw summaries of those papers): 1. A germline heterozygous GPR161 loss-of-function allele is present in all cells. Demonstrated in patients (PMID:31609649). 2. This leads to a somatic loss of the wild-type allele in a cerebellar lineage, mainly by copy-neutral LOH of 1q. Demonstrated in the patients' tumors, which all showed LOH at GPR161. 3. Biallelic loss of GPR161 removes a ciliary G-protein-coupled receptor that normally constitutively activates cAMP and PKA. Mouse data (Mukhopadhyay 2013): "Gpr161 constitutively activates cAMP formation…" 4. Loss of PKA activity reduces Gli3 repressor formation. Mouse: "Gpr161 knockout embryos lack Gli3 repressor." 5. This results in unrestrained, Smoothened-independent Hedgehog pathway activity. Inferred for human tumors. It matches the SHH-subgroup restriction and the absence of other somatic drivers. 6. Expansion and hyperproliferation of cerebellar granule neuron progenitors follows. Mouse (Shimada 2018): conditional deletion in neural stem cells or granule cell progenitors "increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors." 7. Tumors arise, and tumor incidence and severity are higher with earlier deletion. Mouse (Shimada 2018). Early embryonic onset fits the infant presentation in humans [inference].

Suggested ontology terms (look up each before binding): - Cell types: cerebellar granule cell precursor (CL), neural stem cell. - GO processes: smoothened signaling pathway, adenylate cyclase-activating G protein-coupled receptor signaling, cilium-dependent signaling. - Anatomy: cerebellum (UBERON). - Cellular component: primary cilium.

Not covered. Immune, metabolic, omics, single-cell, and CRISPR-screen data [gap].

7. Anatomical structures affected

Organ and cell level. Cerebellum, with granule neuron progenitors as the likely cell of origin [inference from mouse data, plus the usual SHH-medulloblastoma biology].
Cell of origin is derived from the pathograph in dismech. Mark the somatic second-hit node variant_origin: SOMATIC and bind the cell type there.
Lateralization. [gap]

8. Temporal development

Onset. Infancy, median 1.5 years (PMID:31609649).
Progression, staging, and remission. [gap]
Critical period. Infancy is the period of tumor presentation. The mechanism of the age restriction is [gap].

9. Inheritance and population

Inheritance. Autosomal dominant predisposition with a somatic second hit. Penetrance [gap].
Because penetrance is unknown, 5% of infant SHH cases carrying these variants does not give a penetrance figure.
Frequency among cases. The paper reports about 5% of infant SHH medulloblastoma in its cohorts. A 2024 review reports 3.4% of pediatric SHH medulloblastoma (PMC11341988, snippet only).
These figures use different denominators: infant SHH versus pediatric SHH.
Carrier frequency. About 1 in 42,000 to 1 in 125,000, as quoted from the paper above.
Incidence and prevalence of the syndrome. [gap]
De novo versus inherited, parental carriers, family history, founder effects, and sex ratio. [gap]. The paper began from families, so a familial component is implied, but I did not read the pedigree details.

10. Diagnostics

Germline testing. A review recommends it: "patients with MB_SHH should be tested for germline ELP1 mutations, especially those presenting outside of infancy, and for germline GPR161 mutations, particularly those presenting in infancy" (PMC7658916).
Tumor LOH or 1q copy-neutral LOH is a flag for GPR161 deficiency (PMID:31609649).
Tumor diagnostics. The standard medulloblastoma workup applies.
The molecular subgroup is SHH. Methylation profiling is the usual classifier [inference, not source-checked].
Differential. SUFU, PTCH1, and TP53 germline predisposition, and ELP1 for older SHH patients.
Surveillance protocols. [gap]. I found no GPR161-specific surveillance guideline. Do not borrow SUFU or PTCH1 protocols without saying so.

11. Outcome and prognosis

[gap]. No GPR161-specific survival or functional-outcome data were found. The same applies to prognostic factors and the quality-of-life measures.

12. Treatment

No GPR161-specific treatment is documented [gap].
Dismech curation note. Do not transfer SHH-inhibitor (SMO) logic to this entry as a treatment claim.
The mouse mechanism implies the defect lies downstream of Smoothened [inference]. If so, SMO inhibitors would be unlikely to work. That is a hypothesis, not a finding.
Standard infant medulloblastoma therapy and clinical trials [gap].

13. Prevention

Prevention and counseling. Genetic counseling and cascade testing are standard for AD predisposition, but I have no GPR161-specific guidance [gap].
Radiation caution. There is no GPR161 evidence on radiation sensitivity [gap]. Do not extrapolate from other syndromes.

14. Other species

Naturally occurring disease. [gap]. Check OMIA.
Ortholog. A mouse ortholog exists (Gpr161). NCBI Gene IDs were not looked up.

15. Model organisms

Germline knockout mouse (Mukhopadhyay 2013, summary only).
Embryonic lethal by E10.5, with "ventralization throughout the rostro-caudal extent of the neural tube", craniofacial abnormalities, and open fore/mid brain regions and caudal neural tube defects.
Evidence class: model organism.
Conditional deletion (Shimada 2018, Cell Reports, seen as scite report 29386106).
Deletion in neural stem cells or granule cell progenitors increased granule cell progenitor production.
"Earlier deletion of Gpr161 during embryogenesis increased tumor incidence and severity." Evidence class: model organism.
Fidelity to human disease: mouse tumors versus human infant SHH-medulloblastoma [gap]. The cilium-dependence finding is mouse-specific.
Ciliary-localization knock-in (eLife, via search summary). A ciliary-localization-defective but cAMP-competent allele showed progenitor expansion in the intermediate neural tube that depends on Gli3 repressor loss. This suggests ciliary localization matters.
Human-model mismatch.
The heterozygous carrier phenotype in mice is not described in my sources.
Whether the human neural tube defect signal is real is open.
Consider a HUMAN_MODEL_MISMATCH discussion on these.

Curation leads, not yet checked

Read the full text of PMID:31609649 and copy the variant list.
Verify the PMIDs of Shimada 2018 and Mukhopadhyay 2013. Neither PMID is verified.
Run just clingen-list and check ClinVar for GPR161.
Fetch the cohort and survivor reviews and confirm the 3.4% figure.
Search for GPR161 papers after 2021, which my searches did not surface.
Confirm MONDO:1010204.

Sources: - Begemann et al., PubMed 31609649 - PMC6943973 - Cancer Discovery 9(12):1645 - PMC7658916 - PMC11341988 - PanelApp panel 259 - Shimada 2018 (scite) - Mukhopadhyay lab summary - eLife knock-in study

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	4
Resolved	4
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	0
Quoted claims not found in source	1
References weighed for topical relevance	4
On topic	4
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

PMC:PMC7658916: "patients with MB_SHH should be tested for germline ELP1 mutations, especially those presenting outside of infancy, and for germline GPR161 mutations, particularly those presenting in infancy"
closest text in source: "Furthermore, we suggest that patients with MBSHH should be tested for germline ELP1 mutations, especially those presenting outside of infancy, and for germline GPR161 mutations, particularly those presenting in infancy"

Term Validation

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

Outcome	Count
Terms checked	2
Resolved	2
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0

Every term resolved, and every label the report gave matched.

GPR161-related medulloblastoma predisposition

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GPR161-related medulloblastoma predisposition: research report

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species

15. Model organisms

Curation leads, not yet checked

Reference Validation

Quotes not found in the cited source

Term Validation