Submissions for variant NM_000169.3(GLA):c.640-1G>A

dbSNP: rs398123216

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000733701	SCV000861794	pathogenic	not provided	2018-06-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781421	SCV000919439	pathogenic	Fabry disease	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: GLA c.640-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 183379 control chromosomes (gnomAD). c.640-1G>A has been reported in the literature in multiple individuals affected with Fabry Disease (example: Shabbeer_2006, Sawada_2015, Pensabene_2016, and Frabasil_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781421	SCV000962384	pathogenic	Fabry disease	2024-08-03	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the GLA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Fabry disease (PMID: 16595074, 26631895). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 597544). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000733701	SCV002024327	pathogenic	not provided	2019-01-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000781421	SCV002054426	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000781421	SCV002813226	pathogenic	Fabry disease	2021-12-02	criteria provided, single submitter	clinical testing