Submissions for variant NM_000169.3(GLA):c.281G>T (p.Cys94Phe)

dbSNP: rs113173389

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201250	SCV001372351	likely pathogenic	Fabry disease	2021-02-04	criteria provided, single submitter	clinical testing	Variant summary: GLA c.281G>T (p.Cys94Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 22139 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.281G>T has been reported in the literature in cis with another upstream pathogenic variant (c.273_276del TGAT, p.I90MfsTer25) in multiple individuals from one Chinese family affected with Fabry Disease mimicking as familial episodic pain (Mao_2016). Although the co-occurrence with another upstream pathogenic variant in cis (GLA c.273_276del TGAT, p.I90MfsTer25), provides inconclusive evidence supporting the role of this variant in isolation, subsequently, this variant has also been reported in isolation in a 25 year old male with peripheral neuropathy and end-stage renal failure, requiring Hemodialysis (HD), who was diagnosed with Fabry Disease based on extensive clinical and biochemical follow-up supported by results from the molecular analysis (Gaballa_2020). These data indicate that the variant in isolation may be associated with disease. Other amino acid changes at Cys 94, such as p.Cys94Arg, p.Cys94Ser and p.Cys94Tyr have been reported in patients with Fabry Disease (HGMD and Fabry Disease databases), indicating the functional relevance of this residue to overall function. At least one publication reports experimental evidence evaluating an impact of this variant in isolation on protein function. The most pronounced variant effect results in <1% of normal activity (Gaballa_2020). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201250	SCV002165844	likely pathogenic	Fabry disease	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 94 of the GLA protein (p.Cys94Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 27531472, 32699723). ClinVar contains an entry for this variant (Variation ID: 933191). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function with a positive predictive value of 80%. This variant disrupts the p.Cys94 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 21598360, 26415523, 31321922), which suggests that this may be a clinically significant amino acid residue. 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.