ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.870G>C (p.Met290Ile) (rs869312438)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 uncertain significance not specified 2020-12-03 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) and in another female heterozygote with significant symptoms of Fabry disease (Wang_GLA_GinM_2007). 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. Different 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 VUS-possibly pathogenic.

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