ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.545T>G (p.Met182Arg)

gnomAD frequency: 0.00001  dbSNP: rs763208217
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002048749 SCV002315871 pathogenic not provided 2024-05-22 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 182 of the MUT protein (p.Met182Arg). This variant is present in population databases (rs763208217, gnomAD 0.007%). This missense change has been observed in individual(s) with methylmalonic aciduria (Invitae). 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: 1522733). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina RCV003314719 SCV004014684 likely pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2023-05-15 criteria provided, single submitter clinical testing The MMUT c.545T>G (p.Met182Arg) missense variant has not, to our knowledge, been reported in the peer-reviewed literature and is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The p.Met182Arg variant is located in a known functional domain (PMID: 27167370). This variant was identified in trans with a pathogenic variant in this proband who has a phenotype consistent with methylmalonic aciduria. Based on the available evidence, the c.545T>G (p.Met182Arg) variant is classified as likely pathogenic for methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency.

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