ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.1700A>C (p.Tyr567Ser) (rs752537626)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169344 SCV000220707 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2014-09-17 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723436 SCV000331025 pathogenic not provided 2016-03-16 criteria provided, single submitter clinical testing
Invitae RCV000169344 SCV000829446 pathogenic Galactosylceramide beta-galactosidase deficiency 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 567 of the GALC protein (p.Tyr567Ser). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and serine. This variant is present in population databases (rs752537626, ExAC 0.006%). This variant has been reported in the homozygous or compound heterozygous state in several individuals affected with Krabbe disease (PMID: 9338580, 22520351). This variant is also known in the literature as Y551S. ClinVar contains an entry for this variant (Variation ID: 188969). Experimental studies have shown that this missense change causes defects on GALC processing and trafficking (PMID: 27126738, 26865610). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000169344 SCV000915657 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2017-10-23 criteria provided, single submitter clinical testing The GALC c.1700A>C (p.Tyr567Ser) missense variant has been reported in three studies in which it is identified in a total of five individuals with Krabbe disease, four of whom were noted to have the infantile-onset form of the disorder, including one homozygote, two compound heterozygotes, and two heterozygotes in whom a second variant was not identified (Wenger et al. 1997; Tappino et al. 2010; Duffner et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.000111 in the European (non-Finnish) population of the Genome Aggregation Database. Shin et al. (2016) performed expression studies in HEK293T cells and showed that the p.Tyr567Ser variant protein is predominantly present in the unprocessed precursor form and does not accumulate in the lysosome but mislocalizes to the endoplasmic reticulum and Golgi. They also found that GALC activity of the variant protein was significantly reduced compared to the wild type protein in both whole cell lysates and lysosome fractions. Expression studies of the p.Tyr567Ser variant in HEK293T cells showed incorrect protein folding and secretion in multiple polymorphic backgrounds and experiments in transiently transfected HeLa cells revealed that the p.Tyr567Ser variant results in dysfunctional trafficking regardless of the polymorphic background (Spratley et al. 2016). Based on the collective evidence, the p.Tyr567Ser variant is classified as likely pathogenic for Krabbe disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000169344 SCV000919389 pathogenic Galactosylceramide beta-galactosidase deficiency 2018-03-08 criteria provided, single submitter clinical testing Variant summary: GALC c.1700A>C (p.Tyr567Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant of interest had an observed allele frequency of 5.4e-05 in 276212 control chromosomes (gnomAD), which does not exceed the maximum expected allele frequency for a pathogenic GALC variant of 0.0022. The variant, c.1700A>C, has been reported in the literature in compound heterozygote and homozygote individuals affected with Krabbe Disease (Duffner_2011, Duffner_2012, Tappino_2010, and Wenger_1997). In addition, patients were indicated to have significant decrease in GALC activity (Tappino_2010). These data indicate that the variant is likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000169344 SCV000733403 pathogenic Galactosylceramide beta-galactosidase deficiency no assertion criteria provided clinical testing

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