Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001812948 | SCV001472583 | likely pathogenic | not provided | 2020-01-09 | criteria provided, single submitter | clinical testing | The MMUT c.1276G>A; p.Gly426Arg variant (rs769922244) is reported in the literature in at least one individual affected with methylmalonic aciduria (Worgan 2006). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 426 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate destabilization of the protein and reduced activity (Forny 2014, Worgan 2006). Additionally, another variant at this codon (c.1277G>A; p.Gly426Glu) has been reported in the homozygous state in an individual with methylmalonic aciduria (Forny 2016). Based on available information, this variant is considered to be likely pathogenic. References: Forny P et al. Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency. Hum Mutat. 2014 Dec;35(12):1449-58. Forny P et al. Molecular Genetic Characterization of 151 Mut-Type Methylmalonic Aciduria Patients and Identification of 41 Novel Mutations in MUT. Hum Mutat. 2016 Aug;37(8):745-54. Worgan LC et al. Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat. 2006 Jan;27(1):31-43. |
| Labcorp Genetics |
RCV001812948 | SCV002243203 | pathogenic | not provided | 2023-02-14 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 426 of the MUT protein (p.Gly426Arg). This variant is present in population databases (rs769922244, gnomAD 0.0009%). This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 16281286, 27167370). ClinVar contains an entry for this variant (Variation ID: 993879). 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. Experimental studies have shown that this missense change affects MUT function (PMID: 25125334). This variant disrupts the p.Gly426 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27167370). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317472 | SCV004020518 | pathogenic | Methylmalonic acidemia | 2023-06-05 | criteria provided, single submitter | clinical testing | Variant summary: MUT c.1276G>A (p.Gly426Arg) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic domain (IPR006098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251312 control chromosomes (gnomAD). c.1276G>A has been reported in the literature in individuals affected with Methylmalonic Acidemia (examples: Worgan_2006 and Forny_2016). At least one publication reports experimental evidence that this variant reduces normal activity of the protein (example: Worgan_2006). A different variant at this codon (c.1277G>A; p.Gly426Glu) has been reported in the homozygous state in an individual with methylmalonic aciduria (Forny_2016) and is classified pathogenic in ClinVar (ID 222932). The following publications have been ascertained in the context of this evaluation (PMID: 16281286, 27167370, 25125334). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |