ClinVar Genomic variation as it relates to human health

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 365 of the GLA protein (p.Tyr365Asn). This variant is present in population databases (rs367658155, gnomAD 0.01%). 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: 449838). 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. 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.

Identified in hemizygous state in a patient with suspected Fabry disease (Stiles et al., 2020); however, enzyme activity and biomarker analysis suggest this patient was unaffected; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32418857)

Variant summary: GLA c.1093T>A (p.Tyr365Asn) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183406 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1093T>A has been reported in the literature in an individual suspected of having Fabry Disease but determined to be unaffected based on normal enzymatic activity levels (Stiles_2020). This report does not provide unequivocal conclusions about association of the variant with Fabry Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32418857). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces tyrosine with asparagine at codon 365 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 been reported in one individual who was suspected of having Fabry disease (PMID: 32418857). This variant has been identified in 2/205202 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.

The p.Y365N variant (also known as c.1093T>A), located in coding exon 7 of the GLA gene, results from a T to A substitution at nucleotide position 1093. The tyrosine at codon 365 is replaced by asparagine, an amino acid with dissimilar properties. This variant has been identified in a male from a cohort of individuals with clinical suspicion of Fabry disease, however the individual was reportedly unaffected due to normal enzyme and biomarker analysis results (Stiles AR et al. Mol Genet Metab, 2020 07;130:209-214). Based on data from gnomAD, the A allele has an overall frequency of 0.0010% (2/205202) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0105% (2/18978) of African alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.