rs431905509
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_005984.5(SLC25A1):c.844C>T(p.Arg282Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,612,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282H) has been classified as Pathogenic.
Frequency
Consequence
NM_005984.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A1 | NM_005984.5 | c.844C>T | p.Arg282Cys | missense_variant | 9/9 | ENST00000215882.10 | |
SLC25A1 | NM_001256534.2 | c.865C>T | p.Arg289Cys | missense_variant | 8/8 | ||
SLC25A1 | NM_001287387.2 | c.535C>T | p.Arg179Cys | missense_variant | 9/9 | ||
SLC25A1 | NR_046298.3 | n.768C>T | non_coding_transcript_exon_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A1 | ENST00000215882.10 | c.844C>T | p.Arg282Cys | missense_variant | 9/9 | 1 | NM_005984.5 | P1 | |
SLC25A1 | ENST00000451283.5 | c.535C>T | p.Arg179Cys | missense_variant | 9/9 | 2 | |||
SLC25A1 | ENST00000470922.5 | n.986C>T | non_coding_transcript_exon_variant | 8/8 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250708Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135604
GnomAD4 exome AF: 0.0000712 AC: 104AN: 1460796Hom.: 0 Cov.: 33 AF XY: 0.0000826 AC XY: 60AN XY: 726728
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74338
ClinVar
Submissions by phenotype
2-hydroxyglutaric aciduria Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 12, 2020 | This variant was identified as compound heterozygous with NM_005984.5:c.578C>T. - |
Likely pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jul 23, 2019 | ACMG codes: PS3, PM2, PM3, PP3 - |
D,L-2-hydroxyglutaric aciduria Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Feb 14, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 04, 2013 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2023 | 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) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2021 | 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 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. Experimental studies have shown that this missense change affects SLC25A1 function (PMID: 9031613, 29238895). 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. ClinVar contains an entry for this variant (Variation ID: 42194). This missense change has been observed in individuals with combined D-2- and L-2-hydroxyglutaric aciduria (PMID: 23561848, 29238895). This variant is present in population databases (rs431905509, ExAC 0.005%). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at