rs752537626

chr14-87941529-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000153.4(GALC):c.1700A>C(p.Tyr567Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000685 in 1,591,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 3.99

Genes affected

GALC (HGNC:4115): (galactosylceramidase) This gene encodes a lysosomal protein which hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Mutations in this gene have been associated with Krabbe disease, also known as globoid cell leukodystrophy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000153.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 14-87941529-T-G is Pathogenic according to our data. Variant chr14-87941529-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87941529-T-G is described in Lovd as [Pathogenic]. Variant chr14-87941529-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.1700A>C	p.Tyr567Ser	missense_variant	15/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.1700A>C	p.Tyr567Ser	missense_variant	15/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000523 AC: 13 AN: 248668 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000730 AC: 105 AN: 1439134 Hom.: 0 Cov.: 32 AF XY: 0.0000725 AC XY: 52 AN XY: 717478

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000583

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000898

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74252

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:8 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	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). 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) performed at Invitae 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. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 17, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 23, 2017	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. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 9338580, 20886637, 26865610, 27126738) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	26
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.81	D;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.8	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Pathogenic	0.88
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.96	P;P;P;.
Vest4		0.86
MVP		0.93
MPC		0.49
ClinPred		0.47	T
GERP RS		4.6
Varity_R		0.48
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752537626; hg19: chr14-88407873;