ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.433dup (p.Thr145fs) (rs1555383679)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668697 SCV000793341 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2017-08-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668697 SCV000919392 pathogenic Galactosylceramide beta-galactosidase deficiency 2018-04-27 criteria provided, single submitter clinical testing Variant summary: GALC c.433dupA (p.Thr145AsnfsX43) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.628A>T (p.Arg210X), c.1814dupA (p.Tyr605X)). The variant was absent in 245842 control chromosomes (gnomAD). The c.433dupA has been reported in the literature in an individual affected with Krabbe Disease (Puckett 2012). This publication also reported evidence evaluating an impact on protein function, demonstrating a severely decreased galactocerebrosidase activity measured in leukocytes (<10% of normal activity). 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 pathogenic.
Invitae RCV000668697 SCV001582254 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-10-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr145Asnfs*43) in the GALC gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Krabbe disease (PMID: 22115770). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It is also known as c.384_385insA in the literature. ClinVar contains an entry for this variant (Variation ID: 553285). 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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