Submissions for variant NM_000255.4(MMUT):c.295A>G (p.Met99Val)

gnomAD frequency: 0.00001  dbSNP: rs1467385866

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521248	SCV000618822	likely pathogenic	not provided	2017-07-12	criteria provided, single submitter	clinical testing	The M99V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M99V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M99V variant occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (G94R, G94V, P95R) have been reported in the Human Gene Mutation Database in association with MMA (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret the M99V variant as likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000521248	SCV001542281	uncertain significance	not provided	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with valine at codon 99 of the MUT protein (p.Met99Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MUT-related conditions. ClinVar contains an entry for this variant (Variation ID: 450265). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586758	SCV005076897	uncertain significance	not specified	2024-04-09	criteria provided, single submitter	clinical testing	Variant summary: MUT c.295A>G (p.Met99Val) results in a conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic domain (IPR006098) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251442 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.295A>G in individuals affected with Methylmalonic Acidemia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 450265). Based on the evidence outlined above, the variant was classified as uncertain significance.