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

dbSNP: rs771489305

Total submissions: 6

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	2024-01-19	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. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). This variant is present in population databases (rs771489305, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with GALC-related conditions (PMID: 9338580). ClinVar contains an entry for this variant (Variation ID: 188826). 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	2022-01-10	criteria provided, single submitter	clinical testing	Functional studies of this variant showed only residual GALC activity (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)
Natera, Inc.	RCV000169172	SCV002093623	pathogenic	Galactosylceramide beta-galactosidase deficiency	2021-06-23	no assertion criteria provided	clinical testing
GeneReviews	RCV000169172	SCV004035018	not provided	Galactosylceramide beta-galactosidase deficiency		no assertion provided	literature only