Submissions for variant NM_000169.3(GLA):c.475T>C (p.Phe159Leu)

dbSNP: rs1928321516

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001185366	SCV001351561	uncertain significance	Fabry disease	2023-12-05	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces phenylalanine with leucine at codon 159 of the GLA protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001185366	SCV001398516	uncertain significance	Fabry disease	2024-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 159 of the GLA protein (p.Phe159Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GLA-related conditions. ClinVar contains an entry for this variant (Variation ID: 924167). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. This variant disrupts the p.Phe159 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Genome-Nilou Lab	RCV001185366	SCV002054354	uncertain significance	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002327443	SCV002633652	uncertain significance	Cardiovascular phenotype	2022-09-06	criteria provided, single submitter	clinical testing	The p.F159L variant (also known as c.475T>C), located in coding exon 3 of the GLA gene, results from a T to C substitution at nucleotide position 475. The phenylalanine at codon 159 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004731099	SCV005336034	uncertain significance	GLA-related disorder	2024-06-28	no assertion criteria provided	clinical testing	The GLA c.475T>C variant is predicted to result in the amino acid substitution p.Phe159Leu. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.