Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000826043 | SCV000967535 | uncertain significance | not specified | 2018-07-18 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Met329Val variant in AAAS has been reported in 2 individuals with Succinate-CoA ligase de ficiency (Nogueira 2015, Huang 2017), including 1 homozygous individual and 1 in dividual who was compound heterozygous with a variant of uncertain significance. This variant has been identified in 0.03% (11/34384) of Latino chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200167311). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro assays suggest an impact to protein function, including reduced protein l evels (Nogueira 2015, Huang 2017); however, these types of assays may not accura tely represent biological function. Additional computational prediction tools an d conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summar y, while there is some suspicion for a pathogenic role, the clinical significanc e of this variant is uncertain. ACMG/AMP criteria applied: PP1, PP3, PS3_Support ing, PM3_Supporting |
| Labcorp Genetics |
RCV001858414 | SCV002237423 | pathogenic | Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria | 2023-12-07 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 329 of the SUCLA2 protein (p.Met329Val). This variant is present in population databases (rs200167311, gnomAD 0.03%). This missense change has been observed in individuals with succinate-CoA ligase deficiency (PMID: 24659738, 26475597, 27913098). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 667329). 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 SUCLA2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Revvity Omics, |
RCV001858414 | SCV003813405 | likely pathogenic | Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria | 2022-06-21 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV004702468 | SCV005201288 | uncertain significance | not provided | 2023-06-20 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26409464, 26475597, 27913098, 33300680, 24659738) |