Submissions for variant NM_000153.4(GALC):c.169G>A (p.Gly57Ser)

gnomAD frequency: 0.00001  dbSNP: rs11623

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000498062	SCV000224158	pathogenic	not provided	2014-10-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000498062	SCV000589329	pathogenic	not provided	2021-10-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: cells expressing the G57S variant have undetectable GALC activity in comparison to wild type (Lissens et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as Gly41Ser (G41S); This variant is associated with the following publications: (PMID: 27638593, 27126738, 17579360, 21070211)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173074	SCV000695672	pathogenic	Galactosylceramide beta-galactosidase deficiency	2016-03-10	criteria provided, single submitter	clinical testing	Variant summary: The GALC c.169G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 5/5 in-silico tools predict damaging outcome for this variant. This variant has been reported in at least 5 patients with late onset Krabbe disease in both homozygous and compound heterozygous state. This variant was not found in 16310 control chromosomes. In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Invitae	RCV000173074	SCV003784050	pathogenic	Galactosylceramide beta-galactosidase deficiency	2023-12-05	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 57 of the GALC protein (p.Gly57Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Krabbe disease (PMID: 17579360, 21070211). This variant is also known as c.121G>A; p.Gly41Ser. ClinVar contains an entry for this variant (Variation ID: 193054). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 27126738). This variant disrupts the p.Gly57 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000498062	SCV004236684	pathogenic	not provided	2023-03-31	criteria provided, single submitter	clinical testing
GeneReviews	RCV000173074	SCV004035013	not provided	Galactosylceramide beta-galactosidase deficiency		no assertion provided	literature only