ClinVar Miner

Submissions for variant NM_000178.4(GSS):c.-9+5G>A

dbSNP: rs1555889738
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587316 SCV000695767 pathogenic Inherited glutathione synthetase deficiency 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The GSS c.-9+5G>A variant involves the alteration of a conserved nucleotide in the intron that resides in the 5'UTR of the gene. One in silico tool predicts a damaging outcome for this variant. 2/5 splice prediction tools predict a significant impact on normal splicing, while ESE finder predicts that this variant does not significantly impact ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. One publication studied 41 patients with glutathione synthetase (GS) deficiency and found 3 patients who were homozygous for the variant of interest, each of whom had ~10% or less of normal GS activity levels in their cultured fibroblasts (Njalsson_Hum Genet_2005). In each case, the alleles were inherited from heterozygous parents. This variant is absent in the large control database ExAC (0/107328 control chromosomes) as well as ClinVar. Taken together, this variant is classified as pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV000587316 SCV001547501 pathogenic Inherited glutathione synthetase deficiency 2021-03-22 criteria provided, single submitter clinical testing
GeneDx RCV004794418 SCV005414712 pathogenic not provided 2024-05-16 criteria provided, single submitter clinical testing Published functional studies demonstrate two abnormal splicing products and significantly decreased enzyme activity in patient fibroblasts (PMID: 14635114); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33726816, 14635114)
Labcorp Genetics (formerly Invitae), Labcorp RCV005091535 SCV005836927 pathogenic Glutathione synthetase deficiency with 5-oxoprolinuria 2024-02-05 criteria provided, single submitter clinical testing This variant occurs in a non-coding region of the GSS gene. It does not change the encoded amino acid sequence of the GSS protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with glutathione synthetase deficiency (PMID: 14635114). ClinVar contains an entry for this variant (Variation ID: 495702). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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