ClinVar Genomic variation as it relates to human health

This missense variant replaces leucine with phenylalanine at codon 331 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 3/183424 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.L331F variant (also known as c.991C>T), located in coding exon 6 of the GLA gene, results from a C to T substitution at nucleotide position 991. The leucine at codon 331 is replaced by phenylalanine, an amino acid with highly similar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.0016% (3/183424) total alleles studied, with no hemizygote(s) observed. The highest observed frequency was 0.0037% (3/81926 ) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Found in patient having exome sequencing for an unrelated indication. No known history of Fabry disease. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.

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.

The p.Leu331Phe variant in GLA has not been previosuly reported in individuals with Fabry disease, but it has been identified in 0.0037% (3/81926) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs730880437). 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 been reported in ClinVar as likely benign by GeneDx and a VUS by the University of Washington Medical Center (ID: 180828). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was detected in 1 unaffected individual in ClinVar, suggesting that this variant is not pathogenic for Fabry disease. In summary, the clinical significance of the p.Leu331Phe is uncertain. CMG/AMP Criteria applied: PM2_supporting, BS2_supporting (Richards 2015).

This sequence change replaces leucine with phenylalanine at codon 331 of the GLA protein (p.Leu331Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs730880437, ExAC 0.006%). 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: 180828). 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 phenylalanine 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.