ClinVar Miner

Submissions for variant NM_172250.3(MMAA):c.833G>A (p.Gly278Asp)

gnomAD frequency: 0.00001  dbSNP: rs761964238
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667825 SCV000792330 uncertain significance Methylmalonic aciduria, cblA type 2017-06-14 criteria provided, single submitter clinical testing
Invitae RCV000667825 SCV001373260 pathogenic Methylmalonic aciduria, cblA type 2022-03-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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: 552542). This missense change has been observed in individual(s) with methylmalonic aciduria cobalamin A type (PMID: 23716945; 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 (rs761964238, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 278 of the MMAA protein (p.Gly278Asp).
Fulgent Genetics, Fulgent Genetics RCV000667825 SCV002778317 uncertain significance Methylmalonic aciduria, cblA type 2021-08-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000667825 SCV003808841 uncertain significance Methylmalonic aciduria, cblA type 2023-01-12 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003403549 SCV004118712 likely pathogenic MMAA-related condition 2023-01-11 criteria provided, single submitter clinical testing The MMAA c.833G>A variant is predicted to result in the amino acid substitution p.Gly278Asp. This variant was reported in the homozygous state in two individuals with methylmalonic acidemia, cblA type (Girisha et al. 2012. PubMed ID: 23716945; Şeker Yılmaz et al. 2021. PubMed ID: 33453710) and functional studies support pathogenicity of the p.Gly278Asp substitution (Ruetz et al. 2019. PubMed ID: 31056463). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-146575159-G-A). Taken together, this variant is interpreted as likely pathogenic.

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