Submissions for variant NM_000153.4(GALC):c.1814dup (p.Tyr605Ter)

gnomAD frequency: 0.00002  dbSNP: rs766007316

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781391	SCV000919386	likely pathogenic	Galactosylceramide beta-galactosidase deficiency	2017-10-31	criteria provided, single submitter	clinical testing	Variant summary: The GALC c.1814dupA (p.Tyr605X) variant results in a premature termination codon, predicted to cause a truncated or absent GALC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 2/244526 control chromosomes (gnomAD) at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. An internal patient with Krabbe disease diagnosed as an infant (<1 yo) carried this variant homozygously. A clinical diagnostic laboratory cites the variant with a classification of "pathogenic." Taken together, this variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781391	SCV001382219	pathogenic	Galactosylceramide beta-galactosidase deficiency	2023-08-09	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: 633226). This variant is also known as c.1766dupA. This premature translational stop signal has been observed in individual(s) with Krabbe disease (PMID: 30777126). This variant is present in population databases (rs766007316, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Tyr605*) 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).
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001724154	SCV001959367	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001724154	SCV001975005	pathogenic	not provided		no assertion criteria provided	clinical testing