The relationship between GSS and glutathione synthetase deficiency was evaluated using the ClinGen Clinical Validity Framework as of April 20th, 2019. Glutathione is a tripeptide composed of glutamate, cysteine and glycine. It is present in in most mammalian cells and it is involved in several fundamental biological functions, including protection against oxidative damage (PMID 17397529). Glutathione synthetase deficiency is the most common disorder of glutathione metabolism. It is inherited in an autosomal recessive manner. In its most severe form, glutathione synthetase deficiency is characterized by hemolytic anemia, metabolic acidosis, 5-oxoprolinuria, central nervous system symptoms, and recurrent bacterial infections. However, milder cases, with only mild hemolytic anemia and normal 5-oxoproline levels have also been described (for reviews, see PMIDs 17397529 and 15990954). More than 50 families have been described worldwide (PMID 17397529). Variants in GSS, which encodes glutathione synthetase, were first reported in humans with this condition as early as 1996 (Shi et al, PMID 8896573). Data from 12 patients with 14 unique variants (missense, splicing, nonsense, frameshift, and exon duplication) from 7 publications were curated (Shi et al, 1996, PMID 8896573; Dahl et al, 1997, PMID 9215686; Al-Jishi et al, 1999; PMID 10450861; Li et al, 2015, PMID 25851806; Njålsson et al, 2003; PMID 14635114; Signolet et al, 2016, PMID 27581854; Xia et al, 2018, PMID 29340523). This gene-disease relationship is supported by the biochemical function of glutathione synthetase, resulting in glutathione deficiency and 5-oxoprolinuria in when the enzyme activity is deficient (Snoke et al, 1953; PMID 13061393; Richman et al, 1975, PMID 1112810), as well as functional studies (Ingle et al, 2018; PMID 30581542). In summary, GSS is definitively associated with autosomal recessive glutathione synthetase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on April 26, 2019.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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