ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 27657681, 27532257, 23935525)

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 175 of the GLA protein (p.Asp175Glu). This variant is present in population databases (rs782722844, gnomAD 0.006%). This missense change has been observed in individual(s) with Fabry and/or hypertrophic cardiomyopathy (PMID: 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 573833). 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. Experimental studies have shown that this missense change does not substantially affect GLA function (PMID: 23935525). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

The GLA c.525C>G variant is predicted to result in the amino acid substitution p.Asp175Glu. This variant was reported in a patients with Fabry disease and related cardiac phenotypes (Lukas et al. 2013. PubMed ID: 23935525; Patient 5 in Patel et al. 2015. PubMed ID: 25655062; Azevedo et al. 2020. PubMed ID: 32531501). In one case, a patient was noted to also have variants in other HCM gene (Azevedo et al. 2020. PubMed ID: 32531501; Patient 101 in Supplementary Table 2, Mademont-Soler et al. 2017. PubMed ID: 28771489). Functional analysis of this variant showed that enzymatic activity was mildly impacted and ~90% compared to wildtype (Lukas et al. 2013. PubMed ID: 23935525). This variant is reported in 0.0061% of alleles in individuals of European, including five hemizygous individuals (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-100656642-G-C) which is likely too frequent to be associated with high penetrance. In ClinVar, this variant has conflicting interpretations regarding its pathogenicity ranging from likely benign to uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/573833/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This missense variant replaces aspartic acid with glutamic acid at codon 175 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). Functional studies have shown that this variant causes partial reduction of GLA enzyme activity (PMID: 23935525, 31036492). However, clinical relevance of this observation is not known. This variant has been reported in two unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32531501). This variant has also been identified in 6/183473 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.D175E variant (also known as c.525C>G), located in coding exon 3 of the GLA gene, results from a C to G substitution at nucleotide position 525. The aspartic acid at codon 175 is replaced by glutamic acid, an amino acid with highly similar properties. This variant has been detected in multiple individuals with hypertrophic cardiomyopathy (HCM), some of whom have variants in other cardiac genes (Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Walsh R et al. Genet. Med., 2017 02;19:192-203; Azevedo O et al. Am. Heart J., 2020 08;226:114-126). This variant was also identified in a male individual with Anderson-Fabry disease who had sudden cardiac death (Patel V et al. Heart, 2015 Jun). Based on data from gnomAD, the G allele has an overall frequency of 0.003% (6/183473) total alleles studied, with 5 hemizygotes observed. The highest observed frequency was 0.02208% (1/4530) of Other alleles. This amino acid position is 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.