ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.2026G>A (p.Ala676Thr) (rs147715336)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000696572 SCV000825137 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 676 of the MUT protein (p.Ala676Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs147715336, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in individuals affected with methylmalonic acidemia (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000696572 SCV001322636 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.

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