Submissions for variant NM_000169.3(GLA):c.613C>G (p.Pro205Ala)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002293713	SCV002586609	likely pathogenic	not provided	2022-09-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with non-classical Fabry disease in the published literature (Onay et al., 2020); This variant is associated with the following publications: (PMID: 32813676)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003097834	SCV002983586	uncertain significance	Fabry disease	2023-09-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 205 of the GLA protein (p.Pro205Ala). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLA protein function. ClinVar contains an entry for this variant (Variation ID: 1711995). This missense change has been observed in individual(s) with Fabry disease (PMID: 32813676). This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.Pro205 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8875188, 15776423, 18205205, 21598360). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
All of Us Research Program, National Institutes of Health	RCV003097834	SCV005426152	uncertain significance	Fabry disease	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 205 in the substrate binding region of the GLA protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one male individual affected with non-classical Fabry disease (PMID: 32813676). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Pro205Thr, is considered to be disease-causing (ClinVar variation ID: 42456), suggesting that proline at this position is important for GLA protein function. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.