Submissions for variant NM_000169.3(GLA):c.601T>G (p.Ser201Ala)

gnomAD frequency: 0.00003  dbSNP: rs782164447

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001190980	SCV001358649	uncertain significance	Fabry disease	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces serine with alanine at codon 201 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 5/181798 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001190980	SCV003458674	uncertain significance	Fabry disease	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 201 of the GLA protein (p.Ser201Ala). This variant is present in population databases (rs782164447, gnomAD 0.04%). 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: 927590). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.Ser201 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 16595074), which suggests that this may be a clinically significant amino acid residue. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486963	SCV004240699	uncertain significance	Cardiomyopathy	2022-11-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004629479	SCV005123520	uncertain significance	Cardiovascular phenotype	2024-04-02	criteria provided, single submitter	clinical testing	The p.S201A variant (also known as c.601T>G), located in coding exon 4 of the GLA gene, results from a T to G substitution at nucleotide position 601. The serine at codon 201 is replaced by alanine, an amino acid with 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. Based on data from gnomAD, the G allele has an overall frequency of 0.0028% (5/181798) total alleles studied, with 4 hemizygote(s) observed. The highest observed frequency was 0.0361% (5/13841) of East Asian alleles. Based on the available evidence, the clinical significance of this alteration remains unclear.