Submissions for variant NM_000153.4(GALC):c.955del (p.Tyr319fs)

dbSNP: rs786204454

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169089	SCV000220268	likely pathogenic	Galactosylceramide beta-galactosidase deficiency	2014-04-24	criteria provided, single submitter	literature only
GeneDx	RCV000255073	SCV000321694	pathogenic	not provided	2022-06-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant decrease in enyme activity when compared to wild type (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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26795590, 9338580, 16759875, 27638593, 17579360)
Invitae	RCV000169089	SCV001393346	pathogenic	Galactosylceramide beta-galactosidase deficiency	2023-08-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188767). This variant is also known as 906delT, c.907delT. This premature translational stop signal has been observed in individual(s) with Krabbe disease (PMID: 9338580). This variant is present in population databases (rs786204454, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Tyr319Metfs*6) in the GALC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461).
Revvity Omics, Revvity	RCV000255073	SCV002021220	pathogenic	not provided	2020-07-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169089	SCV002819942	pathogenic	Galactosylceramide beta-galactosidase deficiency	2022-12-05	criteria provided, single submitter	clinical testing	Variant summary: GALC c.955delT (p.Tyr319MetfsX6) 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 4e-06 in 248972 control chromosomes. c.955delT has been reported in the literature in individuals affected with Krabbe Disease (e.g. Wenger_1997, Lissens_2007, Fiumara_2011, Orsini_2016). At least one publication reports experimental evidence evaluating an impact on protein function (Saavedra-Martiz_2016). The most pronounced variant effect results in <5% of normal GALC enzymatic activity. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.