Submissions for variant NM_000153.4(GALC):c.1114G>T (p.Ala372Ser)

dbSNP: rs759286485

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001117091	SCV001275249	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2017-09-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001117091	SCV001810428	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2021-07-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV002261280	SCV002541228	uncertain significance	not provided	2021-04-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001117091	SCV002787197	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2022-01-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001117091	SCV003507531	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2024-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 372 of the GALC protein (p.Ala372Ser). This variant is present in population databases (rs759286485, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with GALC-related conditions. ClinVar contains an entry for this variant (Variation ID: 885479). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GALC protein function. 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.
Revvity Omics, Revvity	RCV002261280	SCV003816303	uncertain significance	not provided	2021-04-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490077	SCV004241531	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: GALC c.1114G>T (p.Ala372Ser) results in a conservative amino acid change located in the Glycosyl hydrolase family 59, central domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1114G>T has been reported in the literature in individuals affected with Krabbe Disease. These report(s) do not provide unequivocal conclusions about association of the variant with low GALC activity (Orsini_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26795590). Six 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 uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001117091	SCV005086720	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Krabbe disease (MIM#245200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 10 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Glyco_hydro_59M (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. A change to threonine has been reported in ClinVar as VUS by diagnostic laboratories. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been detected in a newborn screening cohort in a baby with low GALC activity, however it is unclear whether a second hit was identified (PMID: 26795590). In addition, it has been regarded as a VUS in ClinVar by multiple diagnostic laboratories. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Breakthrough Genomics, Breakthrough Genomics	RCV002261280	SCV005193874	uncertain significance	not provided		criteria provided, single submitter	not provided
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001117091	SCV005373835	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2024-09-22	criteria provided, single submitter	clinical testing