ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.1472del (p.Lys491fs) (rs771489305)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169172 SCV000220403 pathogenic Galactosylceramide beta-galactosidase deficiency 2014-06-10 criteria provided, single submitter literature only
Invitae RCV000169172 SCV001391938 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-08-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys491Argfs*62) in the GALC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs771489305, ExAC 0.07%). This variant has been observed in individuals affected with GALC-related conditions (PMID: 9338580). ClinVar contains an entry for this variant (Variation ID: 188826). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169172 SCV001554514 pathogenic Galactosylceramide beta-galactosidase deficiency 2021-03-19 criteria provided, single submitter clinical testing Variant summary: GALC c.1472delA (p.Lys491ArgfsX62) 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. The variant allele was found at a frequency of 5.6e-05 in 248960 control chromosomes. c.1472delA has been reported in the literature in individuals affected with Krabbe Disease (e.g. Wenger_1997, Beltran-Quintero_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence indicating that the variant results in reduced GALC activity when expressed in-vitro (e.g. Saavedra-Martiz_2016). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001541362 SCV001759350 pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing Functional studies of this variant transfected into COS1 cells showed only residual GALC activity that was comparable to mock transfected cells (reported using alternate nomenclature) (Saavedra-Matiz et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27638593, 9338580)

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