ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.370-2A>C

dbSNP: rs730880444
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001293592 SCV001482208 likely pathogenic Fabry disease 2021-02-02 criteria provided, single submitter clinical testing Variant summary: GLA c.370-2A>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: Four predict the variant abolishes the canonical 3' acceptor site. Four predict the variant strengthens an alternate cryptic exonic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 183294 control chromosomes. To our knowledge, no occurrence of c.370-2A>C in individuals affected with Fabry Disease and no experimental evidence demonstrating its impact on protein function have been reported. Of note, a different variant, c.370-2A>G at this location has been reported in individuals with Fabry disease (HGMD database). 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.
Invitae RCV001293592 SCV002156209 pathogenic Fabry disease 2021-02-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with Fabry disease (PMID: 28728877, 15776423, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 2 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).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.