ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1898T>G (p.Val633Gly)

gnomAD frequency: 0.00001  dbSNP: rs200055428
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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, Inc. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.