Submissions for variant NM_000255.4(MMUT):c.1963C>T (p.Arg655Cys)

gnomAD frequency: 0.00007  dbSNP: rs541001298

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001160810	SCV001322639	uncertain significance	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2018-01-13	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.
Elsea Laboratory, Baylor College of Medicine	RCV001250072	SCV001424184	uncertain significance	Peroxisome biogenesis disorder 8A (Zellweger); Peroxisome biogenesis disorder 8B	2020-04-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001160810	SCV002815861	uncertain significance	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-05-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002557373	SCV003278763	pathogenic	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 655 of the MUT protein (p.Arg655Cys). This variant is present in population databases (rs541001298, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of methylmalonic aciduria (internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 909634). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV004032848	SCV004968379	likely benign	not specified	2023-10-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001160810	SCV005440581	uncertain significance	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_Supporting+PP4+PP3