Submissions for variant NM_000169.3(GLA):c.3G>A (p.Met1Ile)

dbSNP: rs2147487910

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375575	SCV001572466	likely pathogenic	Fabry disease	2021-04-08	criteria provided, single submitter	clinical testing	Variant summary: GLA c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183327 control chromosomes. c.3G>A has been reported in the literature in at-least two male individuals affected with Fabry Disease (example, Blanch_1996, Kobayashi_2014). The variant was reported as a de-novo occurrence in one of these affected males (Kobayashi_2014). These data indicate that the variant is likely associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in carrier females (Hossain_2019). The most pronounced variant effect results in 22-45% of normal activity in carrier females. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001375575	SCV003445179	pathogenic	Fabry disease	2022-12-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1065155). Disruption of the initiator codon has been observed in individual(s) with Fabry disease (PMID: 8807334, 12175777, 27896102, 28275245, 31372342). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GLA mRNA. The next in-frame methionine is located at codon 42.
Ambry Genetics	RCV004629626	SCV005123517	pathogenic	Cardiovascular phenotype	2024-05-21	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the GLA gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This alteration has been reported in individuals with Fabry disease, including a de novo occurrence in one individual (Blanch LC. Hum Mutat. 1996;8(1):38-43; Kobayashi M. Mol Genet Metab Rep. 2014 Aug 2;1:283-287). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.