Submissions for variant NM_000169.3(GLA):c.999+2T>C

dbSNP: rs886044860

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000317291	SCV000340423	pathogenic	not provided	2016-03-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000984268	SCV002230935	pathogenic	Fabry disease	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the GLA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. 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: 10666480, 27992580). This variant is also known as IVS6+2; IVS6+2T>C. ClinVar contains an entry for this variant (Variation ID: 286849). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the GLA protein in which other variant(s) (p.Thr412Ile) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984268	SCV002547879	pathogenic	Fabry disease	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: GLA c.999+2T>C 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 a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 183318 control chromosomes (gnomAD). The variant, c.999+2T>C (aka IVS6+2T>C) has been reported in the literature in individuals affected with Fabry Disease (Topaloglu_1999, Liu_2013, Fall_2016, Germain_2020). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27992580, 32161151, 12786754, 23591357, 10666480). ClinVar contains an entry for this variant (Variation ID: 286849). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000317291	SCV003826383	pathogenic	not provided	2022-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000984268	SCV001132404	pathogenic	Fabry disease	2018-01-30	no assertion criteria provided	clinical testing