rs183105855

Positions:

• chr14-87965582-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_000153.4(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 NM_000153.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:6 B:3
• Conservation: PhyloP100: 3.89

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 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 NM_000153.4
• 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	UniProt
GALC	NM_000153.4	c.956A>G	p.Tyr319Cys	missense_variant	9/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.956A>G	p.Tyr319Cys	missense_variant	9/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152072 Hom.: 0 Cov.: 33

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.: 3 AF XY: 0.00190 AC XY: 257 AN XY: 135064

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.: 14 Cov.: 32 AF XY: 0.00111 AC XY: 807 AN XY: 726952

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: 67 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41 AN XY: 74410

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.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00168 AC: 203

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:7 Uncertain:4 Benign:1

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	- -
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	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
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, no assertion criteria provided	clinical testing	Counsyl	May 02, 2019	- -
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	Invitae	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not provided Pathogenic:2 Uncertain:2 Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 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 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	- -
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:1 Benign: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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D;D
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.8	M;.;.;.
MutationTaster	Benign	0.87	D;D;D;D
PrimateAI	Benign	0.43	T
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	T
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

Other links and lift over

dbSNP: rs183105855; hg19: chr14-88431926;