ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.908+1G>A (rs750524447)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169153 SCV000220380 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2014-06-06 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169153 SCV001362552 pathogenic Galactosylceramide beta-galactosidase deficiency 2019-12-30 criteria provided, single submitter clinical testing Variant summary: GALC c.908+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 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 245538 control chromosomes. c.908+1G>A has been reported in the literature in individuals affected with Krabbe Disease (example, Puckett_2012, Duffner_2012, Africa_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 although one submitter has classified the variant as likely pathogenic before 2014 using overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169153 SCV001588958 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-09-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the GALC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs750524447, ExAC 0.006%). This variant has been observed in individual(s) with Krabbe disease (PMID: 22115770, 22520351, 28547031). This variant is also known as c.860+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 188815). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). For these reasons, this variant has been classified as Pathogenic.

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