rs121909308
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_000178.4(GSS):c.799C>T(p.Arg267Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,128 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R267Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000178.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GSS | NM_000178.4 | c.799C>T | p.Arg267Trp | missense_variant | 9/13 | ENST00000651619.1 | |
GSS | NM_001322494.1 | c.799C>T | p.Arg267Trp | missense_variant | 9/13 | ||
GSS | NM_001322495.1 | c.799C>T | p.Arg267Trp | missense_variant | 9/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GSS | ENST00000651619.1 | c.799C>T | p.Arg267Trp | missense_variant | 9/13 | NM_000178.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251450Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135888
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461128Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18AN XY: 726922
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Glutathione synthetase deficiency with 5-oxoprolinuria Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1996 | - - |
Inherited glutathione synthetase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2023 | Experimental studies have shown that this missense change affects GSS function (PMID: 8896573, 10861239, 30581542). 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 GSS protein function. ClinVar contains an entry for this variant (Variation ID: 8527). This missense change has been observed in individual(s) with glutathione synthetase deficiency (PMID: 8896573, 11445798). This variant is present in population databases (rs121909308, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 267 of the GSS protein (p.Arg267Trp). This variant disrupts the p.Arg267 amino acid residue in GSS. Other variant(s) that disrupt this residue have been observed in individuals with GSS-related conditions (PMID: 31198081), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at