Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001386117 | SCV001586237 | pathogenic | Methylmalonic aciduria, cblA type | 2023-04-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MMAA function (PMID: 28497574). 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 MMAA protein function. ClinVar contains an entry for this variant (Variation ID: 1073197). This missense change has been observed in individual(s) with cobalamin A type methylmalonic aciduria (PMID: 15523652, 28497574; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs200577967, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 145 of the MMAA protein (p.Arg145Gln). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003388009 | SCV004100294 | pathogenic | Methylmalonic acidemia | 2023-09-29 | criteria provided, single submitter | clinical testing | Variant summary: MMAA c.434G>A (p.Arg145Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248586 control chromosomes (gnomAD and publication data). c.434G>A has been reported in the literature in individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2004, Plessl_2017, Marelli_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in low protein expression and instability (Plessl_2017). The following publications have been ascertained in the context of this evaluation (PMID: 17728257, 15523652, 35618652, 28497574). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Baylor Genetics | RCV001386117 | SCV004193086 | likely pathogenic | Methylmalonic aciduria, cblA type | 2023-10-22 | criteria provided, single submitter | clinical testing |