Submissions for variant NM_000169.3(GLA):c.167G>T (p.Cys56Phe)

dbSNP: rs869312258

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	RCV001193044	SCV001361593	uncertain significance	not specified	2019-03-14	criteria provided, single submitter	clinical testing	Variant summary: GLA c.167G>T (p.Cys56Phe) 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 (ACMG PP3). The variant was absent in 178573 control chromosomes (ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.167G>T has been reported in the literature in an individual affected with classic Fabry Disease (Eng_1994). This report does not provide unequivocal conclusions about association of the variant with Fabry Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, based on structural analysis, the variant is predicted to disturb the formation of disulfide bond between C56 and C63, and thus may lead to degradation of the protein before it is transported to the lysosomes (Saito_2013). Additionally, the variant was described as amenable to therapy based on an in vitro assay, according to Galafold (migalastat) insert, which is an FDA approved therapy for Fabry disease. However, the insert also states that the inclusion of a variant in this category does not reflect intepretation of clinical significance in Fabry disease. Therefore, this evidence neither supports nor rules out a pathogenic outcome. 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 uncertain significance until additional clinical data and functional studies become available.
Ambry Genetics	RCV005348077	SCV006010145	likely pathogenic	Cardiovascular phenotype	2025-03-12	criteria provided, single submitter	clinical testing	The p.C56F variant (also known as c.167G>T), located in coding exon 1 of the GLA gene, results from a G to T substitution at nucleotide position 167. The cysteine at codon 56 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was reported in individual(s) with features consistent with Fabry disease (Eng CM et al. Hum Mol Genet, 1994 Oct;3:1795-9). In an assay testing GLA function, this variant showed a functionally abnormal result (Benjamin ER et al. Genet Med, 2017 Apr;19:430-438). Other variant(s) at the same codon, p.C56Y (c.167G>A), have been identified in individual(s) with features consistent with Fabry disease (Davies JP et al. Eur J Hum Genet. 1996 ;4(4):219-24). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.