Submissions for variant NM_000169.3(GLA):c.868A>C (p.Met290Leu)

gnomAD frequency: 0.00001  dbSNP: rs375538532

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000545099	SCV000622195	pathogenic	Fabry disease	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 290 of the GLA protein (p.Met290Leu). This variant is present in population databases (rs375538532, gnomAD 0.002%). This missense change has been observed in individual(s) with Fabry disease (PMID: 21517827). ClinVar contains an entry for this variant (Variation ID: 222434). 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 not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 21517827, 23935525). This variant disrupts the p.Met290 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23935525, 27773586, 28728877, 29307789). 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.
Color Diagnostics, LLC DBA Color Health	RCV000545099	SCV001347096	likely pathogenic	Fabry disease	2023-08-03	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with leucine at codon 290 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that baseline alpha-galactosidase A activity of the mutant protein was ~60-70% of wild type upon heterologous expression in HEK-293 cells (PMID: 21517827, 32198894). This variant has been reported in individuals affected with Fabry disease (PMID: 21517827, 23210910, 23332617, 28069318, 30477121). Different variants affecting the same codon, c.870G>A p.Met290Ile and c.870G>C p.Met290Ile, are considered to be disease-causing (Clinvar variation ID: 222435 and 222436), suggesting that methionine at this position is important for GLA protein function. This variant has been identified in 2/183454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000545099	SCV001422919	likely pathogenic	Fabry disease	2020-01-22	criteria provided, single submitter	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, http://gnomad.broadinstitute.org; 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).
GeneDx	RCV000786316	SCV001873919	likely pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22004918, 21517827, 23935525, 25382311, 28069318, 23210910, 27657681)
Genome-Nilou Lab	RCV000545099	SCV002054802	likely pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002372207	SCV002684480	likely pathogenic	Cardiovascular phenotype	2024-04-29	criteria provided, single submitter	clinical testing	The c.868A>C (p.M290L) alteration is located in coding exon 6 of the GLA gene. This alteration results from an A to C substitution at nucleotide position 868, causing the methionine (M) at amino acid position 290 to be replaced by a leucine (L). Based on data from gnomAD, the C allele has an overall frequency of 0.001% (2/183454) total alleles studied. The highest observed frequency was 0.002% (2/81914) of European (non-Finnish) alleles. This alteration has been detected in individuals reported to have Fabry disease (FD) or features consistent with FD, demonstrating reduced alpha-galactosidase enzyme activity (Ferri, 2012; Zampetti, 2013; Graziani, 2017; Burlina, 2019; Gragnaniello, 2021). This amino acid position is highly conserved in available vertebrate species. In in vitro functional studies, this variant was shown to result in reduced enzyme activity (Ferri, 2012; Lukas, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000545099	SCV002765944	likely pathogenic	Fabry disease	2022-11-26	criteria provided, single submitter	clinical testing	Variant summary: GLA c.868A>C (p.Met290Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183454 control chromosomes (gnomAD). c.868A>C has been reported in the literature in individuals affected with Fabry Disease (e.g. Ferri_2012, Zampetti_2013). These data indicate that the variant is likely to be associated with disease. When expressed in a heterologous HEK293 cell assay, the variant had 11.2% normal activitiy (Ferri_2012). Six ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV000786316	SCV003816855	uncertain significance	not provided	2020-01-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000545099	SCV004825232	likely pathogenic	Fabry disease	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with leucine at codon 290 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that baseline alpha-galactosidase A activity of the mutant protein was ~60-70% of wild type upon heterologous expression in HEK-293 cells (PMID: 21517827, 32198894). This variant has been reported in individuals affected with Fabry disease (PMID: 21517827, 23210910, 23332617, 28069318, 30477121). Different variants affecting the same codon, c.870G>A p.Met290Ile and c.870G>C p.Met290Ile, are considered to be disease-causing (Clinvar variation ID: 222435 and 222436), suggesting that methionine at this position is important for GLA protein function. This variant has been identified in 2/183454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
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; http://gnomad.broadinstitute.org/), 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%).