ClinVar Genomic variation as it relates to human health

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 42 of the GLA protein (p.Met42Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 15492942, 15712228; http//dx.doi.org/10.16966/2380-5498.124). ClinVar contains an entry for this variant (Variation ID: 193056). 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: 27657681). This variant disrupts the p.Met42 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8875188, 12175777, 18205205, 23935525, 26415523, 27560961). 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.

Not observed at significant frequency in large population cohorts (gnomAD); 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: 10666480, 17391432, 25382311, 35653365, 30386727, 15712228, 27657681, 31036492, 15492942)

The p.Met42Leu variant in the GLA gene has been previously reported in two unrelated males with Fabry disease (Rosenthal et al., 2004; Shabbeer, Robinson & Desnick, 2005). Alpha-galactosidase A enzyme activity was tested and reported low in one of the published individuals. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Wellestablished in vitro functional studies of p.Met42Leu variant strongly suggest a deleterious effect to the protein that is sufficient to be disease-causing (Benjamin et al., 2017; Oommen et al., 2019). Additionally, multiple different amino acid changes, p.Met42Ile, p.Met42Thr, and p.Met42Val, have been previously reported as disease-causing at this residue, which suggests another change at this residue, such as p.Met42Leu, may similarly disrupt protein function. The p.Met42Leu variant is located in a region where other pathogenic and likely pathogenic variants have been described without benign variation. Pathogenic and likely pathogenic variants have been described in this region and disrupt the function of GLA, resulting in reduced or absent alpha-galactosidase A enzyme activity. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Met42Leu variant as pathogenic for X-linked Fabry disease based on the information above. [ACMG evidence codes used: PS3; PM1; PM2; PM5; PP4]