chr14-87941529-T-G

Position:

chr14-87941529-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 3.99

Variant links:

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]

GALC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.1700A>C	p.Tyr567Ser	missense_variant	15/17	1	NM_000153.4	P1	P54803-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

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:

AN:

248668

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134904

show subpopulations

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.:

Cov.:

AF XY:

0.0000725

AC XY:

AN XY:

717478

show subpopulations

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:

AN:

152004

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74252

show subpopulations

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.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Pathogenic:8Other:1

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. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 17, 2014	- -
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. -
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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.81

D;.;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.8

M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over