ClinVar Miner

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

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Total submissions: 3
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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 2018-12-18 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.

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