ClinVar Genomic variation as it relates to human health

Variant summary: The GLA c.1088G>A (p.Arg363His) variant involves the alteration of a non-conserved nucleotide. 2/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/88023 control chromosomes (3 hemizygotes) at a frequency of 0.0000341, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLA variant (0.005). This variant has been reported in multiple patients with classic or late-onset Fabry disease. In vitro enyzme activity assay showed this variant led to moderate decrease of enzyme activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. In addition, p.R363C and p.R363P have been reported to associate with Fabry disease, suggesting R363 is critical for GLA function. Taken together, this variant is classified as pathogenic.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

The missense variant p.R363H in GLA (NM_000169.2) has been reported previously in affected individuals with late onset Fabry disease (Blaydon et al 2001; Serebrinsky et al, 2015). In vitro enzyme studies depict a moderate effect on enzyme activity which leads to an attenuated/atypical/late-onset phenotype (Lukas et al, 2013; Riera et al, 2015). I t has been classified as a Pathogenic for the late onset phenotype by the Fabry disease working group (Germain et al,2 020). It has been submitted to ClinVar with conflicting interpretations including VUS/Likely Pathogenic and Pathogenic. It is present in 6 hemizygous males in the gnomAD database. However presence of clinical variability ranging from single organ involvement to ascertainment via family screening could account for the presence of these hemizygous males within the gnomAD database. There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. In silico tools predict the variant to be tolerated and the residue is weakly conserved across species. For these reasons, this variant has been classified as Pathogenic

The p.Arg363His variant in GLA has been reported in at least eight individuals with Fabry disease (PMID: 30477121, 21420783, 11668641, 12175777, 23935525, 28360401, 28302345), segregated with disease in three affected relatives from one family (PMID: 26937405), and has been identified in 0.03% (5/19142) of South Asian chromosomes, including 3 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111422676). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Additionally, this variant has a high prevalence in late-onset cases, which may account for the frequency in gnomAD. This variant has also been reported in ClinVar as Pathogenic by EGL Genetic Diagnostics and Integrated Genetics (Variation ID: 222141). In vitro functional studies provide some evidence that the p.Arg363His variant may slightly impact protein function (PMID: 21598360, 23935525, 19387866). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of individuals hemizygous for this variant is highly specific for Fabry disease based on enzymatic diagnosis consistent with disease (PMID: 30477121, 21420783, 11668641, 12175777, 23935525, 28360401, 28302345). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic despite the higher than expected allele frequency in the general population. ACMG/AMP Criteria applied: BS1_supporting, PP1_moderate, PP4, PS3_supporting, PS4_moderate (Richards 2015).

This missense variant replaces arginine with histidine at codon 363 of the GLA protein. Functional studies have shown the mutant protein to exhibit significantly reduced GLA enzyme activity in vitro (>70% decrease compared to wild type) (PMID: 21598360, 23935525). This variant has been reported in four individuals affected with classic Fabry disease and in ten individuals affected with late-onset Fabry disease (PMID: 11668641, 12175777, 21420783, 26937405, 28360401, 30477121, 33022387, 33163363, 33204599, 33437642, 34545322 ). In all tested carrier individuals, decreased leukocyte GLA enzyme activities and increased plasma biomarker globotriaosylsphingosine (lyso-Gb3) levels were observed (PMID: 19387866, 21420783, 28302345, 33022387, 34199132). This variant has been identified in 10/183364 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg363Cys, has been shown to cause loss of GLA protein function and observed in individuals affected with Fabry disease (ClinVar variation ID: 198401). This indicates that arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 363 of the GLA protein (p.Arg363His). This variant is present in population databases (rs111422676, gnomAD 0.03%). This missense change has been observed in individual(s) with Fabry disease (PMID: 11668641, 12175777, 26937405, 28302345). ClinVar contains an entry for this variant (Variation ID: 222141). 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%. Experimental studies have shown that this missense change affects GLA function (PMID: 19387866, 21598360). This variant disrupts the p.Arg363 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12175777, 21598360, 25835592, 26937405; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The c.1088G>A (p.Arg363His) variant in the GLA gene is located in the exon 7 of the GLA gene and is predicted to replace arginine with histidine at codon 363 of the GLA protein. This variant has been identified in many individuals with Fabry disease (PMID: 30477121, 21420783, 11668641, 12175777, 28360401, 28302345, 36624527, 34545322, 33437642, 33163363), and reported as segregated with disease in three affected relatives from one family (PMID: 26937405). This variant has been reported to be associated with a later-onset and milder course of disease in males (PMID 26937405, 32161151, 32418857). Biochemical testing in patient lymphoblasts showed reduced enzyme activity of 12% to 24% of normal activity (PMID: 19387866, 21598360, respectively). This variant is rare in the general population according to gnomAD v4.0.0 (0.002%). A different variant affecting the same amino acid residue Arg363 (c.1087C>T, p.Arg363Cys) has been determined to be pathogenic in ClinVar according to ACMG guidelines. Therefore, the c.1088G>A (p.Arg363His) variant in the GLA gene has been classified as pathogenic.