ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.956A>G (p.Tyr319Cys) (rs183105855)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507823 SCV000603777 pathogenic not specified 2016-09-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255537 SCV000574984 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing
Counsyl RCV000590447 SCV000800677 uncertain significance Galactosylceramide beta-galactosidase deficiency 2018-03-22 criteria provided, single submitter clinical testing
GeneDx RCV000255537 SCV000322147 pathogenic not provided 2017-07-10 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). The Y319C variant was observed on 1% alleles from individuals of South Asian background in the Exome Aggregation Consortium (ExAC) data set. The Y319C variant is a non-conservative amino acid substitution that alters a position on the surface of the enzyme near the substrate-binding pocket (Deane et al., 2011). In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Y319C as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America 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 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 319 of the GALC protein (p.Tyr319Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs183105855, ExAC 1.0%) at a frequency higher than expected for Krabbe disease. This variant has been observed to segregate with Krabbe disease in 3 small families (PMID: 23197103) and it has also been observed to be homozygous or in combination with another GALC variant individuals affected with Krabbe disease (PMID: 22520351, 27535533, 10234611, 22115770, 11003282). This variant is also known as p.Y303C in the literature. ClinVar contains an entry for this variant (Variation ID: 265349). Experimental studies have shown that this missense change disrupts protein trafficking likely due to protein misfolding (PMID: 27126738). In summary, this variant has been seen in patients with Krabbe disease. However, it occurs at a frequency in the general population that is much higher than expected for this disorder. 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.

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