ClinVar Miner

Submissions for variant NM_005984.5(SLC25A1):c.844C>T (p.Arg282Cys)

gnomAD frequency: 0.00003  dbSNP: rs431905509
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000035018 SCV000992582 likely pathogenic 2-hydroxyglutaric aciduria 2019-07-23 criteria provided, single submitter research ACMG codes: PS3, PM2, PM3, PP3
Institute of Human Genetics, University of Leipzig Medical Center RCV000035018 SCV001934316 pathogenic 2-hydroxyglutaric aciduria 2020-11-12 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous with NM_005984.5:c.578C>T.
Labcorp Genetics (formerly Invitae), Labcorp RCV001852702 SCV002290314 likely pathogenic not provided 2021-10-11 criteria provided, single submitter clinical testing This variant is present in population databases (rs431905509, ExAC 0.005%). This missense change has been observed in individuals with combined D-2- and L-2-hydroxyglutaric aciduria (PMID: 23561848, 29238895). ClinVar contains an entry for this variant (Variation ID: 42194). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC25A1 function (PMID: 9031613, 29238895). This variant disrupts the p.Arg282 amino acid residue in SLC25A1. Other variant(s) that disrupt this residue have been observed in individuals with SLC25A1-related conditions (PMID: 23393310, 23561848, 29238895), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces arginine with cysteine at codon 282 of the SLC25A1 protein (p.Arg282Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine.
GeneDx RCV001852702 SCV004036393 pathogenic not provided 2023-03-21 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on enzyme activity (Pop et al., 2018; Majd et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 29238895, 23561848, 34930662, 29031613)
Neuberg Centre For Genomic Medicine, NCGM RCV001801242 SCV004175826 pathogenic D,L-2-hydroxyglutaric aciduria 2023-02-14 criteria provided, single submitter clinical testing
OMIM RCV001801242 SCV000058658 pathogenic D,L-2-hydroxyglutaric aciduria 2013-04-04 no assertion criteria provided literature only

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