Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000627817 | SCV000748694 | pathogenic | Fabry disease | 2018-06-28 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan with cysteine at codon 47 of the GLA protein (p.Trp47Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Fabry disease in a family (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Two additional missense substitution at this codon (p.Trp47Gly, p.Trp47Arg) have been reported in individuals affected with Fabry disease and has been shown to affect protein function (PMID: 11668641, 27211852). This suggests that the tryptophan residue is critical for GLA protein function and that missense substitutions at this position may be pathogenic. For these reasons, this variant has been classified as Pathogenic. |