Submissions for variant NM_004208.4(AIFM1):c.1355T>C (p.Val452Ala)

gnomAD frequency: 0.00001  dbSNP: rs1356446773

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001166265	SCV001328628	uncertain significance	Severe X-linked mitochondrial encephalomyopathy	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001214647	SCV001386336	uncertain significance	Charcot-Marie-Tooth Neuropathy X; Combined oxidative phosphorylation deficiency	2019-06-07	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with AIFM1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 452 of the AIFM1 protein (p.Val452Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine.
Ambry Genetics	RCV002379665	SCV002689295	uncertain significance	Inborn genetic diseases	2019-08-30	criteria provided, single submitter	clinical testing	The p.V452A variant (also known as c.1355T>C), located in coding exon 13 of the AIFM1 gene, results from a T to C substitution at nucleotide position 1355. The valine at codon 452 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.