ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.868A>C (p.Met290Leu) (rs375538532)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000545099 SCV000622195 uncertain significance Fabry disease 2017-01-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 290 of the GLA protein (p.Met290Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs375538532, ExAC 0.002%). This variant has been reported in an individual affected with Fabry disease (PMID: 21517827). Experimental studies have shown that this change reduces α-galactosidase activity (PMID: 21517827, 23935525). In summary, this variant is a rare missense change that has a deleterious effect on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000545099 SCV001347096 uncertain significance Fabry disease 2019-01-10 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786316 SCV000925089 uncertain significance not provided 2017-06-26 no assertion criteria provided provider interpretation Seen in 1 patient in our center with dilated cardiomyopathy. Testing was performed at Invitae. Given the weak case data and different phenotype than would be expected for a disease-causing variant in these gene, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The GLA gene encodes alphagalacotosidase. Mutations in the GLA cause Fabry disease, an X-linked condition characterized by multi-organ dysfunction. Clinical characteristics include left ventricular hypertrophy, kidney failure, peripheral neuropathy, ophthalmologic and sweating abnormalities. The variant has been seen in at least 1 unrelated case of Fabry disease. It has not been reported in any cases of dilated cardiomyopathy. There is weak case data and some functional data. Ferri et al 2011 reported the variant in a patient with clinical findings suggestive of Fabry disease. She was a 34yo, who had "cardiovascular manifestations, psychiatric symptoms, and cardiomyopathy (type not specified). Her alpha-gal A enzyme level was 11nmol/mg/h. The paper noted that the HEK cells harboring the Met290Leu variant had decreased enzyme levels that were recovered with treatment with the pharmacologic chaperone deoxygalactonojirimycin (DGJ). Lukas et al (2013) found that variant resulted in a 18% wild type alpha-gal A level on in vitro assay. The Met at codon 290 is conserved across species. PolyPhen predicts it to be probably damaging. The variant is present in 2 of 89,369 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >140,00 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 2 of 40,064 individuals of European descent (MAF = 0.002%).
Broad Institute Rare Disease Group, Broad Institute RCV000545099 SCV001422919 likely pathogenic Fabry disease 2020-01-22 no assertion criteria provided curation The p.Met290Leu variant in GLA has been reported in eight individuals with Fabry disease, has segregated with disease in 7 affected relatives from 2 families (PMID: 23210910, 28069318), and has been identified in 0.0024% (2/81914) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs375538532). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS by Invitae (Variation ID:222434). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype that is consistent with disease (PMID: 21517827). One additional likely pathogenic variant, causing a different amino acid change at the same position, p.Met290Ile, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 28302345, 23935525, 22773828, 27560961, 16595074). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP3, PM2_supporting, PP4, PS4_supporting, PP1_moderate, PM5_supporting (Richards 2015).

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