ClinVar Genomic variation as it relates to human health

Variant summary: GLA c.547G>A (p.Gly183Ser) 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 183417 control chromosomes (gnomAD). c.547G>A has been reported in the literature in multiple individuals affected with Fabry Disease (example: Shabbeer_2002, Tuttolomondo_2017, Sayer_2008, Benjamin_2009, Duro_2018, Jain_2018). Few of these patients were presented with a classic phenotype. These data indicate that the variant is very likely to be associated with disease. The variant resulted in very low enzymatic activity both in patients and in in vitro cell based assays (example: Shabbeer_2002, Wu_2011, Tuttolomondo_2017, Sayer_2008, Benjamin_2009). One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. In the HGMD database, there are several other variants affecting the same codon and nearby codons (example: p.G183A , p.G183R , p.G183D , p.G183V, p.Y184N, p.L180V ) suggesting this area might be mutational hotspot. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.G183S pathogenic mutation (also known as c.547G>A), located in coding exon 3 of the GLA gene, results from a G to A substitution at nucleotide position 547. The glycine at codon 183 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in unrelated males reported to have features consistent with Fabry disease (FD) including reduced enzyme activity, and females with this variant have also been reported to have some features of FD (Shabbeer J et al. Mol Genet Metab, 2002 May;76:23-30; Sayer JA et al. Kidney Int, 2008 Nov;74:1366; Benjamin ER et al. J Inherit Metab Dis, 2009 Jun;32:424-40; McCloskey S et al. F1000Res, 2018 Mar;7:356; Tuttolomondo A et al. Oncotarget, 2017 Sep;8:61415-61424; Jain R et al. JACC Cardiovasc Imaging, 2018 Apr;11:644-647; Moiseev S et al. Nephron, 2019 Jan;141:249-255). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). These nucleotide and amino acid positions are highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.