ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.430del (p.Ile144fs) (rs775277935)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255375 SCV000230032 pathogenic not provided 2014-05-13 criteria provided, single submitter clinical testing
GeneDx RCV000255375 SCV000321683 pathogenic not provided 2016-06-14 criteria provided, single submitter clinical testing The c.430delA pathogenic variant in the GALC gene has been reported previously in association with Krabbe Disease (Orsini et al., 2016). The c.430delA deletion causes a frameshift starting with codon Isoleucine 144, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Ile144LeufsX27. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Invitae RCV001059225 SCV001223845 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-10-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile144Leufs*27) in the GALC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs775277935, ExAC 0.005%). This variant has been observed in individuals affected with Krabbe disease (PMID: 9338580, 30777126). This variant is also known as 382delA in the literature. ClinVar contains an entry for this variant (Variation ID: 197110). 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 RCV001059225 SCV001362551 pathogenic Galactosylceramide beta-galactosidase deficiency 2019-06-07 criteria provided, single submitter clinical testing Variant summary: GALC c.430delA (p.Ile144LeufsX27) 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 1.6e-05 in 249270 control chromosomes. c.430delA has been reported in the literature in multiple individuals affected with Krabbe Disease (Wenger_1997, Orsini_2016, Bascou_2018, Beltran-Quintero_2019). To our knowledge, no experimental evidence demonstrating a variant specific impact on protein function has been reported although almost all reported compound heterozygote patients had an enzymatically confirmed diagnosis of Krabbe Disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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