20-34936976-T-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000178.4(GSS):āc.656A>Gā(p.Asp219Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,760 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D219A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000178.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GSS | NM_000178.4 | c.656A>G | p.Asp219Gly | missense_variant | 7/13 | ENST00000651619.1 | |
GSS | NM_001322494.1 | c.656A>G | p.Asp219Gly | missense_variant | 7/13 | ||
GSS | NM_001322495.1 | c.656A>G | p.Asp219Gly | missense_variant | 7/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GSS | ENST00000651619.1 | c.656A>G | p.Asp219Gly | missense_variant | 7/13 | NM_000178.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151964Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251476Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461796Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727210
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151964Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74198
ClinVar
Submissions by phenotype
Inherited glutathione synthetase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 23, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 219 of the GSS protein (p.Asp219Gly). This variant is present in population databases (rs28938472, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp219 amino acid residue in GSS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9215686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GSS function (PMID: 15056072). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GSS protein function. ClinVar contains an entry for this variant (Variation ID: 8531). This missense change has been observed in individual(s) with glutathione synthetase deficiency (PMID: 8896573, 11167850, 15717202). It has also been observed to segregate with disease in related individuals. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 13, 2020 | Variant summary: GSS c.656A>G (p.Asp219Gly) results in a non-conservative amino acid change located in the Glutathione synthase, substrate-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251476 control chromosomes. c.656A>G has been reported in the literature in multiple individuals affected with Glutathione Synthetase Deficiency (ie. Njalsson_2005, Corrons_2001, Shi_1996). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Aug 25, 2019 | - - |
Glutathione synthetase deficiency without 5-oxoprolinuria Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2001 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at