Submissions for variant NM_000153.4(GALC):c.956A>G (p.Tyr319Cys)

gnomAD frequency: 0.00019  dbSNP: rs183105855

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255537	SCV000322147	uncertain significance	not provided	2023-07-03	criteria provided, single submitter	clinical testing	One of the most common variants observed in individuals identified by newborn screening, where it was always observed on the same allele (in cis) with the p.(D248N) variant; however, these individuals have not developed Krabbe disease in childhood (Orsini JJ et al., 2016; Thompson-Stone R et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27126738, 27535533, 27638593, 22520351, 34426522, 23197103, 11003282, 26795590, 33832819, 35002157, 34670123, 33178108, 31069529, 35460079, 36920572)
CeGaT Center for Human Genetics Tuebingen	RCV000255537	SCV000574984	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	GALC: BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507823	SCV000603777	pathogenic	not specified	2016-09-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590447	SCV000695680	pathogenic	Galactosylceramide beta-galactosidase deficiency	2017-03-01	criteria provided, single submitter	clinical testing	Variant summary: The GALC c.956A>G (p.Tyr319Cys) variant (alternatively also known Y303C) involves the alteration of a conserved nucleotide and is located in catalytic domain of the protein (via InterPro). Structural analysis shows that it is located in substrate-binding pocket (Deane_2011, PMID: 21876145). 5/5 in silico tools predict damaging outcome for this variant. This variant was found in 203/120350 control chromosomes (including 2 homozygotes) from ExAC and it was relatively more commonly found in South Asian subpopulation at an allele frequency of 0.010246 (169/16494). In literature, this variant is reported in patients with late- or later-onset Krabbe disease in compound heterozygosity with other pathogenic variants, including cosegregation with disease in two families (Debs_2012, Duffner_2012). In a cohort of 348 infants with low GALC activity referred for diagnostic testing in a study of newborn screening for Krabbe disease in New York state, this variant was found with an allele frequency of 6.8% (47/696 chromosomes), suggesting it is a recurrent mutation (Orsini_2016). One in vitro functional study shows that this variant leads to a significant decrease in enzymatic activity (Saavedra-Matiz_2016). Absent or significantly reduced GALC enzyme activity was also detected in a patient who had this variant and a second splice-site variant on the other allele (Duffner_2012). One clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae	RCV000590447	SCV000815534	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 319 of the GALC protein (p.Tyr319Cys). This variant is present in population databases (rs183105855, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Krabbe disease (PMID: 11003282, 22520351, 23197103, 27535533). This variant is also known as p.Y303C. ClinVar contains an entry for this variant (Variation ID: 265349). 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) has been performed at Invitae 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.
Mendelics	RCV000590447	SCV001139496	pathogenic	Galactosylceramide beta-galactosidase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000590447	SCV001163748	likely pathogenic	Galactosylceramide beta-galactosidase deficiency		criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000507823	SCV001251713	benign	not specified	2020-05-03	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000590447	SCV001435231	likely benign	Galactosylceramide beta-galactosidase deficiency		criteria provided, single submitter	research	The heterozygous p.Tyr319Cys variant in GALC has been identified in an individual in the compound heterozygous state with 20% of normal GALC enzyme activitiy and Krabbe disease (PMID: 22520351), and has been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive Krabbe disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000255537	SCV001714488	uncertain significance	not provided	2023-02-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000590447	SCV001716346	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2021-05-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255537	SCV002025243	likely pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000255537	SCV002064462	pathogenic	not provided	2019-06-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the GALC gene demonstrated a sequence change, c.956A>G, in exon 9 that results in an amino acid change, p.Tyr319Cys. This sequence change has been described in the gnomAD database with a population frequency of 0.13% (dbSNP rs183105855). This is a common pathogenic sequence change that has previously been described in multiple patients with later-onset Krabbe disease in the homozygous and compound heterozygous states. These patients had absent or significantly reduced galactocerebrosidase activity (PMIDs: 22520351, 22115770). Experimental studies have demonstrated that this variant disrupts protein trafficking likely due to protein misfolding (PMID: 27126738). The p.Tyr319Cys change affects a moderately conserved amino acid residue located in a domain of the GALC protein that is known to be functional. The p.Tyr319Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Mutation Taster, REVEL). These collective evidences indicate that this sequence change is pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000590447	SCV002073319	pathogenic	Galactosylceramide beta-galactosidase deficiency		criteria provided, single submitter	clinical testing	The Y319C variant (reported as Y303C due to the use of alternate nomenclature) has been published previously in multiple unrelated individuals with later-onset Krabbe disease and absent or significantly reduced galactocerebrosidase enzyme activity who harbored a second pathogenic variant on the other allele (Debs et al, 2013; Duffner et al, 2012; Farina et al, 2000).In vitro functional studies showed a significant decrease in enzyme activity (Saavedra-Matiz CA et al). The variant has been submitted to ClinVar as Pathogenic. The Y319C variant was observed on 1% alleles from individuals of South Asian background in the Exome Aggregation Consortium (ExAC) data set.In silico analysis predicts the variant to be damaging and the residue is moderately conserved across species. Based on the above the variant is classified as Pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000590447	SCV002500966	likely pathogenic	Galactosylceramide beta-galactosidase deficiency		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000590447	SCV002767240	pathogenic	Galactosylceramide beta-galactosidase deficiency	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The 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) 0115 - Variants in this gene are known to have variable expressivity. Disease severity and age of onset can be highly variable even within families (OMIM; PMID: 33178108) (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (368 heterozygotes, 3 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 59 (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals and is also known as p.(Tyr303Cys) due to alternate nomenclature. The variant has previously been described as pathogenic in multiple individuals with Krabbe disease and is considered to be a hypomorphic allele which results in disease when in trans with a more severe variant (PMIDs: 10234611, 22115770, 22520351, 23197103, 24388568, 26795590, 27638593, 29481565, 30089515, 31093932). However, this variant has also been reported in at least three homozygous patients with juvenile and late-infantile onset phenotype (PMID: 33178108). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies have demonstrated significantly reduced GALC activity in patients, and functional work in transfected cells showed that the variant results in ER retention and is therefore not properly trafficked to lysosomes, likely due to protein misfolding (PMIDs: 10234611, 22520351, 27126738, 30089515). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Counsyl	RCV000590447	SCV000800677	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2019-05-02	no assertion criteria provided	clinical testing