Submissions for variant NM_000169.3(GLA):c.1102G>C (p.Ala368Pro)

dbSNP: rs144994244

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418968	SCV000516031	likely benign	not specified	2015-03-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000468186	SCV000543772	uncertain significance	Fabry disease	2021-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with proline at codon 368 of the GLA protein (p.Ala368Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs144994244, ExAC 0.004%). This variant has not been reported in the literature in individuals affected with GLA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000468186	SCV001358841	uncertain significance	Fabry disease	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 368 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with GLA-related disorders in the literature. This variant has been identified in 4/205199 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000468186	SCV001422794	uncertain significance	Fabry disease	2020-01-22	criteria provided, single submitter	curation	The p.Ala368Pro variant in GLA has not been previously reported in individuals with Fabry disease and has been identified in 0.0043% (4/92620) of European (non-Finnish) chromosomes, including 3 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144994244). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as likely benign by GeneDx and VUS by Invitae (ID: 379288). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala368Pro variant is uncertain. ACMG/AMP Criteria applied: BP4, PM2_supporting (Richards 2015).
Mayo Clinic Laboratories, Mayo Clinic	RCV001507538	SCV001713143	uncertain significance	not provided	2020-06-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000468186	SCV002054470	likely benign	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing