Submissions for variant NM_000153.4(GALC):c.235C>T (p.Arg79Cys)

gnomAD frequency: 0.00041  dbSNP: rs73312829

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000811717	SCV000951998	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the GALC protein (p.Arg79Cys). This variant is present in population databases (rs73312829, gnomAD 0.1%). This missense change has been observed in individual(s) with a positive newborn screening result for GALC-related disease (PMID: 26795590; Invitae). ClinVar contains an entry for this variant (Variation ID: 655524). 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. Experimental studies have shown that this missense change affects GALC function (PMID: 27638593). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282375	SCV002571981	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: GALC c.235C>T (p.Arg79Cys) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 59, catalytic domain (IPR049161) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 249202 control chromosomes, predominantly at a frequency of 0.0009 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GALC causing Krabbe Disease (8e-05 vs 0.0022), allowing no conclusion about variant significance. c.235C>T has been reported in the literature in individuals identified through newborn screening programs as having low GALC enzyme activity, suggesting they are at an increased risk of developing Krabbe Disease (e.g. Orsini_2016, Basheeruddin_2021). However, this variant has exclusively been reported in the literature in cis with the pseudodeficiency variant, c.1685T>C, p.I562T (legacy name c.1637T>C, p.I546T), complicating interpretations of pathogenicity. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Krabbe Disease. An experimental study examining the impact of the variant on protein function found that it had approximately 45% enzyme activity compared to wild-type GALC, whereas when the variant was expressed in cis with the p.I562T variant, the resulting protein had only 10% activity versus the wild-type protein (e.g. Saavedra-Martiz_2016). This suggests that the variant may have a mild effect on enzyme activity in isolation, but the presence or absense of the pseudodefficiency variant may also be an important factor when considering its functional impact. The following publications have been ascertained in the context of this evaluation (PMID: 34065072, 26795590, 27638593, 27171547). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV002538105	SCV003747530	uncertain significance	Inborn genetic diseases	2021-04-28	criteria provided, single submitter	clinical testing	The c.235C>T (p.R79C) alteration is located in exon 2 (coding exon 2) of the GALC gene. This alteration results from a C to T substitution at nucleotide position 235, causing the arginine (R) at amino acid position 79 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV003132077	SCV003808564	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000811717	SCV001454076	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2020-09-16	no assertion criteria provided	clinical testing