rs752560204
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_000178.4(GSS):c.4delG(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
Consequence
NM_000178.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GSS | NM_000178.4 | c.4delG | p.Ala2ProfsTer14 | frameshift_variant | Exon 2 of 13 | ENST00000651619.1 | NP_000169.1 | |
GSS | NM_001322494.1 | c.4delG | p.Ala2ProfsTer14 | frameshift_variant | Exon 2 of 13 | NP_001309423.1 | ||
GSS | NM_001322495.1 | c.4delG | p.Ala2ProfsTer14 | frameshift_variant | Exon 2 of 13 | NP_001309424.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000231 AC: 58AN: 251230Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135816
GnomAD4 exome AF: 0.000109 AC: 160AN: 1461742Hom.: 0 Cov.: 31 AF XY: 0.000122 AC XY: 89AN XY: 727184
GnomAD4 genome AF: 0.000164 AC: 25AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74354
ClinVar
Submissions by phenotype
Glutathione synthetase deficiency with 5-oxoprolinuria Pathogenic:2
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. -
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Inherited glutathione synthetase deficiency Pathogenic:1Uncertain:1
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. -
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;C1856399:Glutathione synthetase deficiency without 5-oxoprolinuria Pathogenic:1
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not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at