ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.124A>C (p.Met42Leu) (rs797044613)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235742 SCV000293385 uncertain significance not provided 2016-07-19 criteria provided, single submitter clinical testing The M42L variant in the GLA gene has been reported in a 65 year-old male with renal insufficiency resulting in proteinuria who was subsequently found to have a low, but detectable, serum alpha-Gal A level (Rosenthal et al., 2004). This individual did not have a family history of disease. This variant was also reported in a male with Fabry disease, however, specific clinical details and family history was not provided (Shabbeer et al., 2005). The M42L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, missense variants in the same residue (M42V, M42T, M42R) and in nearby residues (P40L, T41I, G43S, W44C) have been reported in association with Fabry (Stenson et al., 2014),but the full significance of these variants is unknown. Finally, M42L is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and the effect on alpha-Gal A production and its potential clinical implications is not definitive. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000235742 SCV000331633 pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing
Invitae RCV000809963 SCV000950149 pathogenic Fabry disease 2019-12-01 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 42 of the GLA protein (p.Met42Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Fabry disease including individuals with low alpha-galactosidase enzyme activity, a finding that is highly specific for this condition (PMID: 15492942, 15712228, ClinVar contains an entry for this variant (Variation ID: 193056). Experimental studies have shown that this missense change results in decreased enzyme activity (PMID: 27657681). This variant disrupts the p.Met42 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 12175777, 23935525, 26415523, 18205205, 27560961, 8875188), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics Program, Stanford Medicine RCV000809963 SCV001427212 pathogenic Fabry disease 2019-12-18 no assertion criteria provided clinical testing 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 ( 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]

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