Submissions for variant NM_000255.4(MMUT):c.556A>G (p.Met186Val)

gnomAD frequency: 0.00001  dbSNP: rs148331800

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666525	SCV000790830	uncertain significance	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-04-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000666525	SCV002803978	uncertain significance	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2021-12-02	criteria provided, single submitter	clinical testing
Invitae	RCV002532054	SCV003264919	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 186 of the MUT protein (p.Met186Val). This variant is present in population databases (rs148331800, gnomAD 0.0009%). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 16281286, 21048060, 34668645). ClinVar contains an entry for this variant (Variation ID: 551460). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117467	SCV003800695	uncertain significance	not specified	2023-01-07	criteria provided, single submitter	clinical testing	Variant summary: MUT c.556A>G (p.Met186Val) 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 8e-06 in 251170 control chromosomes (gnomAD). c.556A>G has been reported in the literature as a biallelic genotype in individuals affected with Methylmalonic Acidemia (e.g. Worgan_2006, Hauser_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000666525	SCV004800879	likely pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		no assertion criteria provided	clinical testing	PM2_P+PM3_S+PP3+PP4