rs797044613
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000169.3(GLA):c.124A>G(p.Met42Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Fabry disease Pathogenic:2
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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. -
not provided Pathogenic:1
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GLA-related disorder Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at