| Study | Reported genotype / original notation | NM_001001563.5 normalized notation | Key clinical or functional evidence | Evidence limits |
|---|---|---|---|---|
| [Shahrour et al., 2017](https://doi.org/10.1111/cge.12855) | Homozygous legacy **p.Arg217Trp** or **p.Thr252Met** in four individuals from two consanguineous families | **c.340C>T, p.Arg114Trp** or **c.446C>T, p.Thr149Met** | Infantile-onset seizures, severe developmental impairment, 3-methylglutaconic aciduria, mildly elevated lactate, brain atrophy/basal-ganglia abnormalities, and variable complex-V deficiency; one tested patient had complex-V activity at 54% of control (pqac-00000014, pqac-00000015, pqac-00000016, pqac-00000025) | Only four affected individuals; frequencies are not population estimates. Earlier protein numbering used a longer transcript/isoform and must not be mixed with current canonical numbering. |
| [Reyes et al., 2018](https://doi.org/10.15252/emmm.201708698) | Compound heterozygous **c.335C>A, p.Ser112Ter** and **c.569G>C, p.Gly190Ala** on the legacy transcript; one variant inherited from each parent | **c.26C>A, p.Ser9Ter** and **c.260G>C, p.Gly87Ala** | Rapidly progressive severe encephalopathy with epilepsy and lactic acidosis; fibroblasts had reduced TIMM50/TIM23 components, impaired TIM23-dependent import, lower membrane potential and respiration, and rescue after wild-type TIMM50 expression. The legacy missense allele was reported once among >200,000 alleles; the nonsense allele was absent from ExAC (pqac-00000022, pqac-00000023, pqac-00000029, pqac-00000030) | Single proband; historical and current HGVS coordinates are transcript-specific. Functional rescue supports causality but does not establish clinical treatment efficacy. |
| [Tort et al., 2019](https://doi.org/10.1002/humu.23779) | Compound heterozygous **c.341G>A** and **c.805G>A** | **p.Arg114Gln** and **p.Gly269Ser** | One boy had onset at 2.5–3.5 months, West syndrome, Leigh-like lesions, optic atrophy, persistent 3-MGA/3-methylglutaric aciduria, lactic acidosis, neutropenia and dilated cardiomyopathy; at 17 years he had severe encephalopathy, dystonia and wheelchair dependence. Patient cells showed TIMM50 protein loss, abnormal cristae, reduced OXPHOS assembly and respiration; wild-type TIMM50 rescued the cellular defect (pqac-00000012, pqac-00000021, pqac-00000024) | Single-patient case study; complex activities varied by tissue and normalization method, limiting genotype–phenotype generalization. |
| [Mir et al., 2020](https://doi.org/10.1111/cge.13763) | Apparent homozygous **c.755C>T, p.Thr252Met** under the report’s legacy transcript numbering | Corresponding current canonical notation: **c.446C>T, p.Thr149Met** | One girl developed epileptic spasms at two months with hypsarrhythmia, hypotonia, global developmental delay, microcephaly, marked urinary 3-MGA and lactate of 3 mmol/L. Vigabatrin 150 mg/kg/day produced seizure cessation and EEG normalization; she remained seizure-free after withdrawal at 16 months (pqac-00000013) | Single case without a comparator. **c.755C>T/p.Thr252Met and c.446C>T/p.Thr149Met are transcript-specific representations of the same reported substitution and must not be treated as separate variants.** MRI abnormalities were considered vigabatrin-associated and largely resolved. |
| [Crameri et al., 2024](https://doi.org/10.1080/10985549.2024.2353652) | Homozygous **NM_001001563.5:c.337C>T, p.Arg113Cys** | Same: **c.337C>T, p.Arg113Cys** | One patient had infantile spasms, developmental delay, optic atrophy and generalized white-matter loss, but **urinary 3-MGA was not detected**. The allele had gnomAD v4.0 frequency 0.00001053 with no homozygotes. Fibroblasts showed near-complete TIMM50 loss, impaired TIM23 import, combined OXPHOS and cristae defects, and improvement with wild-type TIMM50 re-expression (pqac-00000005, pqac-00000007, pqac-00000018, pqac-00000026) | Initially classified as a **VUS with potential clinical relevance**; rarity, phenotype, functional impairment and rescue add pathogenic evidence, but the report concerns one patient. Absence of 3-MGA shows that this biomarker is not obligatory. |


*Table: Transcript-aware comparison of key TIMM50-associated MGCA9 reports, emphasizing the very small samples, functional evidence, and the need not to conflate legacy and current HGVS numbering. No PMID or population prevalence is inferred where it was not verified.*