Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000519959 | SCV000617497 | pathogenic | not provided | 2018-05-17 | criteria provided, single submitter | clinical testing | The V633G missense variant in the MUT gene has been reported previously in association with methylmalonic acidemia in individuals who were heterozygous for V633G and second variant in the MUT gene (Adjalla et al., 1998; Worgan et al., 2006; Lempp et al., 2007). Functional analysis of V633G found that is is associated with residual enzyme activity, but significantly reduced affinity for cobalamin (Forny et al., 2014). Additionally, the V633G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, we interpret V633G to be a pathogenic variant. |
Invitae | RCV000519959 | SCV001383120 | pathogenic | not provided | 2023-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 633 of the MUT protein (p.Val633Gly). This variant is present in population databases (rs200055428, gnomAD 0.0009%). This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 9554742, 16281286, 17113806, 30577886). ClinVar contains an entry for this variant (Variation ID: 449393). 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%. Experimental studies have shown that this missense change affects MUT function (PMID: 25125334). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Myriad Genetics, |
RCV001810459 | SCV002060043 | uncertain significance | Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency | 2021-11-16 | criteria provided, single submitter | clinical testing | NM_000255.3(MMUT):c.1898T>G(V633G) is a missense variant classified as a variant of uncertain significance in the context of methylmalonic acidemia, MMUT-related. V633G has been observed in cases with relevant disease (PMID: 16281286, 27167370, 30577886). Functional assessments of this variant are available in the literature (PMID: 25125334, 27167370). V633G has been observed in population frequency databases (gnomAD: NFE 0.001%). In summary, there is insufficient evidence to classify NM_000255.3(MMUT):c.1898T>G(V633G) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. |