Submissions for variant NM_000169.3(GLA):c.870G>C (p.Met290Ile)

gnomAD frequency: 0.00001  dbSNP: rs869312438

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000733247	SCV000861291	pathogenic	not provided	2018-05-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280629	SCV001467860	likely pathogenic	Fabry disease	2021-07-02	criteria provided, single submitter	clinical testing	Variant summary: GLA c.870G>C (p.Met290Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183451 control chromosomes (gnomAD). c.870G>C has been reported in the literature in a female patient with hypertrophic cardiomyopathy in whom lysomal inclusions were reportedly demonstrated in the myocardium (Azevedo_2020), two female patients with late onset Fabry phenotype (Nowak_2019), two female heterozygotes with significant symptoms of Fabry disease and one of whom was diagnosed with the Classic form the disease (Wang_2007, Delarosa-Rodriguez_2021) and also in a female heterozygote without any classic Fabry disease symptoms (Silva_2021). However, none of these studies report X-inactivation studies performed on female patients. Several publications report conflicting experimental evidence evaluating an impact on protein function. Enzymatic activity of Alpha Galactosidase A was found to be reduced at between 10-30% of normal activity in patient derived leukocytes while the activity levels in patient derived plasma were within the reportable normal range (Azevedo_2020). In addition, in an in vitro functional assay another nucleotide change (c.870G>A) with the same codon and amino acid effect (p.Met290Ile) was found to have approximately 40% of enzymatic activity compared to wild-type (Lukas_2013) while another assay expressing the variant in HEK-cells reported activity levels at 68% of normal (Nowak_2019). One of these studies reports the minimal alpha-Gal activity required to avoid Fabry disease as being between 30-35% of the mean control (Nowak_2019), although they express ambiguity on the extent the alpha-Gal activity in HEK 293 cells correlates with in-vivo activities in affected males with Fabry disease. A different nucleotide change resulting in the same protein effect, namely, GLA c.870G>A (p.M290I) has been reported as likely pathogenic in ClinVar and also seen in patients with Fabry Disease in the HGMD database. In addition, several other variants affecting the same codon and nearby codons (example: p.M290L, p.M290V, p.I289V, p.A291T) have been reported in HGMD and ClinVar suggesting this domain might be clinically significant. One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, due to a paucity of evidence supporting a penetrant pathogenic outcome in affected males, and conflicting functional evidence, the variant was classified as likely pathogenic.
Genome-Nilou Lab	RCV001280629	SCV002054801	likely pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001280629	SCV003511409	pathogenic	Fabry disease	2023-04-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 21517827, 23935525). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GLA function (PMID: 22773828). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLA protein function. ClinVar contains an entry for this variant (Variation ID: 222436). This missense change has been observed in individual(s) with Fabry disease (PMID: 16595074, 28646478, 31996269, 33527381, 33907643). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 290 of the GLA protein (p.Met290Ile).
Revvity Omics, Revvity	RCV000733247	SCV003834640	likely pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000733247	SCV001803521	uncertain significance	not provided	2020-10-15	flagged submission	clinical testing	Reported as heterozygous in an individual with late-onset Fabry disease with normal alpha galactosidase A activity and normal LysoGb2 levels (Nowak et al., 2017); Reported as heterozygous in an individual with late-onset Fabry disease and also present in the asymptomatic sisters (Azevedo et al., 2020); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27773586, 32531501, 28728877, 31519519)