chr14-87965582-T-C

Position:

chr14-87965582-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The ENST00000261304.7(GALC):c.956A>G(p.Tyr319Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00079 in 1,613,458 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y319Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00083 ( 14 hom. )

Consequence

GALC
ENST00000261304.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:7B:3

Conservation

PhyloP100: 3.89

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:

GALC (HGNC:):

GALC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000261304.7

BP4

Computational evidence support a benign effect (MetaRNN=0.02430579).

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4 linkuse as main transcript	c.956A>G	p.Tyr319Cys	missense_variant	9/17	ENST00000261304.7	NP_000144.2	P54803-1A0A0A0MQV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 linkuse as main transcript	c.956A>G	p.Tyr319Cys	missense_variant	9/17	1	NM_000153.4	ENSP00000261304.2		P54803-1

Frequencies

GnomAD3 genomes

AF:

0.000454

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00149

AC:

371

AN:

248972

Hom.:

AF XY:

0.00190

AC XY:

257

AN XY:

135064

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000494

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00967

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000443

Gnomad OTH exome

AF:

0.000993

GnomAD4 exome

AF:

0.000827

AC:

1208

AN:

1461268

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

807

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000515

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0100

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000209

Gnomad4 OTH exome

AF:

0.000994

GnomAD4 genome

AF:

0.000440

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00767

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000292

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.00168

AC:

203

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Pathogenic:7Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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).In vitro functional studies showed a significant decrease in enzyme activity (Saavedra-Matiz CA et al). The variant has been submitted to ClinVar as Pathogenic. The Y319C variant was observed on 1% alleles from individuals of South Asian background in the Exome Aggregation Consortium (ExAC) data set.In silico analysis predicts the variant to be damaging and the residue is moderately conserved across species. Based on the above the variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Tyr319Cys variant in GALC has been identified in an individual in the compound heterozygous state with 20% of normal GALC enzyme activitiy and Krabbe disease (PMID: 22520351), and has been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive Krabbe disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	May 02, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Krabbe disease (MIM#245200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Disease severity and age of onset can be highly variable even within families (OMIM; PMID: 33178108) (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (368 heterozygotes, 3 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 59 (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals and is also known as p.(Tyr303Cys) due to alternate nomenclature. The variant has previously been described as pathogenic in multiple individuals with Krabbe disease and is considered to be a hypomorphic allele which results in disease when in trans with a more severe variant (PMIDs: 10234611, 22115770, 22520351, 23197103, 24388568, 26795590, 27638593, 29481565, 30089515, 31093932). However, this variant has also been reported in at least three homozygous patients with juvenile and late-infantile onset phenotype (PMID: 33178108). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies have demonstrated significantly reduced GALC activity in patients, and functional work in transfected cells showed that the variant results in ER retention and is therefore not properly trafficked to lysosomes, likely due to protein misfolding (PMIDs: 10234611, 22520351, 27126738, 30089515). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2022	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 319 of the GALC protein (p.Tyr319Cys). This variant is present in population databases (rs183105855, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Krabbe disease (PMID: 11003282, 22520351, 23197103, 27535533). This variant is also known as p.Y303C. ClinVar contains an entry for this variant (Variation ID: 265349). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GALC protein function. In summary, 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. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not provided

Pathogenic:2Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	GALC: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 19, 2019	DNA sequence analysis of the GALC gene demonstrated a sequence change, c.956A>G, in exon 9 that results in an amino acid change, p.Tyr319Cys. This sequence change has been described in the gnomAD database with a population frequency of 0.13% (dbSNP rs183105855). This is a common pathogenic sequence change that has previously been described in multiple patients with later-onset Krabbe disease in the homozygous and compound heterozygous states. These patients had absent or significantly reduced galactocerebrosidase activity (PMIDs: 22520351, 22115770). Experimental studies have demonstrated that this variant disrupts protein trafficking likely due to protein misfolding (PMID: 27126738). The p.Tyr319Cys change affects a moderately conserved amino acid residue located in a domain of the GALC protein that is known to be functional. The p.Tyr319Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Mutation Taster, REVEL). These collective evidences indicate that this sequence change is pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2024	One of the most common variants observed in individuals identified by newborn screening, where it typically observed on the same allele (in cis) with the p.(D248N) variant; these individuals have not developed Krabbe disease in childhood, but some individuals had psychosine in the intermediate range (PMID: 26795590, 34065072, 33832819); 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: 27126738, 27535533, 27638593, 22520351, 34426522, 23197103, 11003282, 33832819, 35002157, 34670123, 26795590, 33178108, 31069529, 35460079, 36920572, 36964972, 37432431, 34065072) -

not specified

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2016	- -

GALC-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2024

The GALC c.956A>G variant is predicted to result in the amino acid substitution p.Tyr319Cys. This variant has been reported in compound heterozygous states with other potentially pathogenic GALC variants (missense variant and 30-kb gross deletion) in multiple unrelated patients with late-onset Krabbe disease who had reduced enzyme activity (Duffner et al., 2012. PubMed ID: 22520351; Farina et al., 2000. PubMed ID: 11003282). Results obtained from in-vitro studies suggested that the p.Tyr319Cys variant is likely to cause disease due to protein misfolding (Spratley et al., 2016. PubMed ID: 27126738). This variant is reported in 0.97% of alleles in individuals of South Asian descent in gnomAD, including three homozygous individuals (http://gnomad.broadinstitute.org/variant/14-88431926-T-C). However, to date there is no known case of Krabbe disease with homozygous p.Tyr319Cys variant (www.mdpi.com/2409-515X/3/1/3/pdf). This variant has conflicting interpretations of pathogenicity in ClinVar ranging from benign to pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/265349). Although we suspect that this variant may be pathogenic, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

D;D;D;D

MetaRNN

Benign

0.024

T;T;T;T

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.8

M;.;.;.

MutationTaster

Benign

0.87

D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-5.9

D;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.73

MVP

0.99

MPC

0.64

ClinPred

0.13

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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