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

gnomAD frequency: 0.00003  dbSNP: rs752537626

Total submissions: 15

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
Eurofins Ntd Llc (ga)	RCV000723436	SCV000331025	pathogenic	not provided	2016-03-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169344	SCV000829446	pathogenic	Galactosylceramide beta-galactosidase deficiency	2024-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 567 of the GALC protein (p.Tyr567Ser). This variant is present in population databases (rs752537626, gnomAD 0.01%). This missense change has been observed in individuals with Krabbe disease (PMID: 9338580, 22520351). ClinVar contains an entry for this variant (Variation ID: 188969). 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) indicates that this missense variant is expected to disrupt GALC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 26865610, 27126738). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Ambry Genetics	RCV001266084	SCV001444256	pathogenic	Inborn genetic diseases	2024-05-03	criteria provided, single submitter	clinical testing	The c.1700A>C (p.Y567S) alteration is located in coding exon 15 of the GALC gene. This alteration results from an A to C substitution at nucleotide position 1700, causing the tyrosine (Y) at amino acid position 567 to be replaced by a serine (S). Based on data from gnomAD, the C allele has an overall frequency of 0.005% (15/280054) total alleles studied. The highest observed frequency was 0.011% (14/128048) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other GALC variant in individuals with features consistent with Krabbe disease; in at least one instance, the variants were identified in trans (Corre, 2021; Guenzel, 2020; Beltran-Quintero, 2019; Madsen, 2019; Orsini, 2020; Duffner, 2011; Tappino, 2010; Wenger, 1997; Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In vitro functional studies demonstrated that p.Y567S (legacy p.Y551S) by itself or in cis with the p.I562T (legacy p.I546T) polymorphism has a severely detrimental effect on protein folding and secretion, and does not traffic correctly to lysosomes (Spratley, 2016; Shin, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000723436	SCV001762095	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000723436	SCV001782789	pathogenic	not provided	2024-06-24	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced enzyme activity and impaired localization to the lysosome (PMID: 27126738, 26865610); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Y551S); This variant is associated with the following publications: (PMID: 26865610, 20886637, 26795590, 35586607, 32089546, 31240153, 34071213, 9338580, 27126738)
Revvity Omics, Revvity	RCV000723436	SCV002021224	pathogenic	not provided	2020-12-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169344	SCV002776487	pathogenic	Galactosylceramide beta-galactosidase deficiency	2024-06-17	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000169344	SCV004100445	likely pathogenic	Galactosylceramide beta-galactosidase deficiency		criteria provided, single submitter	clinical testing	The missense variant p.Y567S in GALC (NM_000153.4) has been previously reported in homozygous as well as compound heterozygous state in affected individuals with Krabbe disease. Functional studies suggest a damaging effect (Duffner PK et al, Wenger DA et al, Shin D et al). The variant has been submitted to ClinVar as Pathogenic. The p.Y567S variant is observed in 12/1,12,616 (0.0107%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.Y567S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The tyrosine residue at codon 567 of GALC is conserved in all mammalian species. The nucleotide c.1700 in GALC is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000169344	SCV000733403	pathogenic	Galactosylceramide beta-galactosidase deficiency		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169344	SCV001454060	pathogenic	Galactosylceramide beta-galactosidase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723436	SCV001969500	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000169344	SCV004035009	not provided	Galactosylceramide beta-galactosidase deficiency		no assertion provided	literature only