Submissions for variant NM_000153.4(GALC):c.1912G>A (p.Gly638Ser)

gnomAD frequency: 0.00001  dbSNP: rs769851272

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175126	SCV000226558	uncertain significance	not provided	2014-11-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174873	SCV001338272	uncertain significance	not specified	2022-09-14	criteria provided, single submitter	clinical testing	Variant summary: GALC c.1912G>A (p.Gly638Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.9e-05 in 246188 control chromosomes, predominantly at a frequency of 0.00095 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in GALC causing Krabbe Disease (6.9e-05 vs 0.0022), allowing no conclusion about variant significance. c.1912G>A has been reported in the literature in individuals affected with Krabbe Disease. These data indicate that the variant may be associated with 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 uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae	RCV001826881	SCV003522186	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2022-03-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 638 of the GALC protein (p.Gly638Ser). This variant is present in population databases (rs769851272, gnomAD 0.09%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 23197103). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1865G>A, p.Gly622Ser. ClinVar contains an entry for this variant (Variation ID: 194698). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly638 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22115770). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV001826881	SCV002091308	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2020-03-20	no assertion criteria provided	clinical testing