Submissions for variant NM_000153.4(GALC):c.1897dup (p.Thr633fs)

dbSNP: rs1555378538

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487204	SCV000573842	likely pathogenic	not provided	2018-05-17	criteria provided, single submitter	clinical testing	The c.1897dupA variant in the GALC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1897dupA variant causes a frameshift starting with codon Threonine 633, changes this amino acid to a Asparagine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Thr633AsnfsX5. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1897dupA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1897dupA variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae	RCV001851266	SCV002133355	pathogenic	Galactosylceramide beta-galactosidase deficiency	2021-06-26	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with GALC-related conditions. ClinVar contains an entry for this variant (Variation ID: 424065). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the GALC protein. Other variant(s) that disrupt this region (p.Lys648*) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Thr633Asnfs*5) in the GALC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the GALC protein.