Submissions for variant NM_000178.4(GSS):c.1139_1144del (p.Val380_Gln381del)

dbSNP: rs770455024

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV001507982	SCV001713853	pathogenic	not provided	2019-05-09	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PM4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587171	SCV002765948	likely pathogenic	Glutathione synthetase deficiency with 5-oxoprolinuria	2024-04-02	criteria provided, single submitter	clinical testing	Variant summary: GSS c.1139_1144delTACAGG (p.Val380_Gln381del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 1.2e-05 in 251462 control chromosomes.. c.1139_1144delTACAGG has been reported in the literature in the compound heterozygous state in an individual affected with Glutathione Synthetase Deficiency (e.g. Shi_1996). One publication reports experimental evidence evaluating an impact on protein function and found the variant was non-functional, as determined by a yeast complementation assay, and produced a non-soluble protein product (Shi_1996). The following publications have been ascertained in the context of this evaluation (PMID: 11445798, 8896573). ClinVar contains an entry for this variant (Variation ID: 1163159). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002469398	SCV004298056	likely pathogenic	Inherited glutathione synthetase deficiency	2023-12-06	criteria provided, single submitter	clinical testing	This variant, c.1139_1144del, results in the deletion of 2 amino acid(s) of the GSS protein (p.Val380_Gln381del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs770455024, gnomAD 0.02%). This variant has been observed in individual(s) with glutathione synthetase deficiency (PMID: 8896573, 11445798). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 1137del6. ClinVar contains an entry for this variant (Variation ID: 1163159). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GSS function (PMID: 8896573). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.