rs752560204
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_000178.4(GSS):c.4del(p.Ala2ProfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
GSS
NM_000178.4 frameshift
NM_000178.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.89
Genes affected
GSS (HGNC:4624): (glutathione synthetase) Glutathione is important for a variety of biological functions, including protection of cells from oxidative damage by free radicals, detoxification of xenobiotics, and membrane transport. The protein encoded by this gene functions as a homodimer to catalyze the second step of glutathione biosynthesis, which is the ATP-dependent conversion of gamma-L-glutamyl-L-cysteine to glutathione. Defects in this gene are a cause of glutathione synthetase deficiency. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 20-34951848-GC-G is Pathogenic according to our data. Variant chr20-34951848-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 338302.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GSS | NM_000178.4 | c.4del | p.Ala2ProfsTer14 | frameshift_variant | 2/13 | ENST00000651619.1 | NP_000169.1 | |
| GSS | NM_001322494.1 | c.4del | p.Ala2ProfsTer14 | frameshift_variant | 2/13 | NP_001309423.1 | ||
| GSS | NM_001322495.1 | c.4del | p.Ala2ProfsTer14 | frameshift_variant | 2/13 | NP_001309424.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GSS | ENST00000651619.1 | c.4del | p.Ala2ProfsTer14 | frameshift_variant | 2/13 | NM_000178.4 | ENSP00000498303 | P1 |
Frequencies
GnomAD3 genomes 0.000164 AC: 25AN: 152220Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000231 AC: 58AN: 251230Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135816
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GnomAD4 exome AF: 0.000109 AC: 160AN: 1461742Hom.: 0 Cov.: 31 AF XY: 0.000122 AC XY: 89AN XY: 727184
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GnomAD4 genome 0.000164 AC: 25AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74354
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inherited glutathione synthetase deficiency Pathogenic:2Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Ala2Profs*14) in the GSS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GSS are known to be pathogenic (PMID: 12638941, 15717202). This variant is present in population databases (rs752560204, gnomAD 0.5%). This premature translational stop signal has been observed in individual(s) with gluthathione synthetase deficiency (PMID: 8896573). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 338302). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 29, 2016 | Variant summary: The c.4delG (p.Ala2Profs) variant in GSS gene is a nonsense change that results in the loss of the 460 amino acids of GSS (~98%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The results of functional showed less than 10% GSS activity in pts fibroblasts as well as in bacterial expression system. . The variant is present in the large control population dataset of ExAC at a low frequency 0.0002 (25/120304 chrs tested), exclusively in individuals of European descent (0.00038; 15/66140).The latter frequency does not exceed the maximal expected frequency of a pathogenic allele (0.003) in this gene. The variant of interest has been reported in two brothers presented with oxoprolinuria, metabolic acidosis, haemolytic anemia and mental retardation. Taking together, the variant was classified as Pathogenic. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The GSS c.4delG (p.Ala2ProfsTer14) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Ala2ProfsTer14 variant has been reported in one study in which it was found in a compound heterozygous state with a missense variant in two siblings with glutathione synthetase (GS) deficiency. Control data are unavailable for this variant which is reported at a frequency of 0.0004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in E. coli and yeast demonstrate that the variants result in 2% of expression levels and 10% GSS activity as compared to wildtype (Shi et al. 1996). Due to the potential impact of frameshift variants and supporting evidence, the p.Ala2ProfsTer14 variant is classified as a variant of unknown significance but suspicious for pathogenicity for glutathione synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Glutathione synthetase deficiency with 5-oxoprolinuria Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1996 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 22, 2023 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at