ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.124A>G (p.Met42Val)

dbSNP: rs797044613
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000727558 SCV000854791 pathogenic not provided 2018-03-23 criteria provided, single submitter clinical testing
Invitae RCV001063224 SCV001228061 pathogenic Fabry disease 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 42 of the GLA protein (p.Met42Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 8875188, 18205205, 19287194). ClinVar contains an entry for this variant (Variation ID: 222174). 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 expected to disrupt GLA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 19287194, 23935525). This variant disrupts the p.Met43 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15492942, 15712228, 27657681). 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.
Genome-Nilou Lab RCV001063224 SCV002054459 pathogenic Fabry disease 2021-07-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003907777 SCV004724136 pathogenic GLA-related disorder 2024-01-12 criteria provided, single submitter clinical testing The GLA c.124A>G variant is predicted to result in the amino acid substitution p.Met42Val. This variant was reported in individuals with Fabry disease (Davies et al. 1996. PubMed ID: 8875188; Shimotori et al. 2008. PubMed ID: 18205205; Park et al. 2009. PubMed ID: 19287194) and in high-risk screening for Fabry disease (Yoshida et al. 2020. PubMed ID: 32843101). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies suggest this variant impacts protein function (Lukas et al. 2013. PubMed ID: 23935525; Park et al. 2009. PubMed ID: 19287194; Shimotori et al. 2008. PubMed ID: 18205205). Alternate nucleotide changes affecting the same amino acid (p.Met42Leu; p.Met42Thr; p.Met42Arg; p.Met42Ile), have been reported in individuals with Fabry disease (Rosenthal et al. 2004. PubMed ID: 15492942; Shabbeer et al. 2002. PubMed ID: 12175777; Riera et al. 2015. PubMed ID: 25382311; Pan et al. 2016. PubMed ID: 27560961). This variant is interpreted as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.