14-87939915-A-G

Position:

chr14-87939915-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM2PP3PP5_Very_StrongBP4

The ENST00000261304.7(GALC):c.1901T>C(p.Leu634Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000246 in 1,607,104 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L634L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

GALC
ENST00000261304.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.12

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 12 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 ENST00000261304.7

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 14-87939915-A-G is Pathogenic according to our data. Variant chr14-87939915-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.113942355). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4 linkuse as main transcript	c.1901T>C	p.Leu634Ser	missense_variant	16/17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 linkuse as main transcript	c.1901T>C	p.Leu634Ser	missense_variant	16/17	1	NM_000153.4	ENSP00000261304	P1	P54803-1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

151950

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:

0.00870

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000651

AC:

162

AN:

248814

Hom.:

AF XY:

0.000615

AC XY:

AN XY:

135016

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00851

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000241

AC:

351

AN:

1455036

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

181

AN XY:

724352

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00790

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.000283

GnomAD4 genome

AF:

0.000296

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00872

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000444

Hom.:

Bravo

AF:

0.000495

ExAC

AF:

0.000687

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

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:12Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	Across a selection of the available literature, the GALC c.1901T>C (p.Leu634Ser) missense variant, also referred to as p.Leu618Ser, has been identified in 12 individuals affected with Krabbe disease, including in a homozygous state in one individual, in a compound heterozygous state in eight individuals, and in a heterozygous state in three individuals. All affected individuals were of Asian descent and have a variable age of onset of Krabbe disease ranging from late-infantile to adult (Furuya et al. 1997; Satoh et al. 1997; Xu et al. 2006; Hossain et al. 2014; Lim et al. 2016; Yoshimura et al. 2016). The p.Leu634Ser variant was also reported in seven asymptomatic newborns including in five in a homozygous state and in two in a compound heterozygous state (Orsini et al. 2016). In the five asymptomatic homozygous newborns, additional GALC variants were detected in cis with the p.Leu634Ser variant. GALC activity was used to assess risk of developing Krabbe disease, with one infant classified as high-risk, one as low-risk, and three as moderate-risk (Orsini et al. 2016). The p.Leu634Ser variant was absent from 65 controls (Furuya et al. 1997), but is reported at a frequency of 0.01923 in the Japanese population of the 1000 Genomes Project. Expression of the p.Leu634Ser variant in COS-1 cells resulted in an approximately 90% reduction in enzyme activity when compared to wild-type (Furuya et al. 1997; Satoh et al. 1997; Shin et al. 2016). Another study demonstrated lack of secretion of the p.Leu634Ser variant protein in transfected HEK293T cells, and also suggested that presence of the variant reduced trafficking of the GALC protein to lysosomes, although a second study showed localization in lysosomes (Spratley et al. 2016; Shin et al. 2016). Despite the high allele frequency, based on the collective clinical evidence, the p.Leu634Ser 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	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 11, 2022	- -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jul 22, 2023	The observed missense variant c.1901T>Cp.Leu634Ser in GALC gene has been reported previously in individuals with Krabbe disease. Experimental studies have shown that this missense change affects GALC function Lim SM, et al., 2016; Hossain MA, et al., 2014. This variant is reported with the allele frequency 0.06% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic/Benign. The amino acid Leu at position 634 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2016	Variant summary: The GALC c.1901T>C (p.Leu634Ser) variant, alternatively also known was L618S, involves the alteration of a highly conserved nucleotide and is located in Glyco_hydro_59 domain of the protein. 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 83/120532 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0090487 (78/8620). No homozygotes have been reported in general population. In literature, this variant is widely reported as a mild pathogenic variant that causes later-onset Krabbe disease (KD) and is found in several KD patients in homozygous, compound heterozygous and heterozygous states. The variants frequency is high in Japanese patients; a study has reported its allele frequency at 10.7% (11/102 alleles) in a Japanese patient cohort (Hossain_2013). Available functional assays (enzymatic as well as processing assay) further support the variant as a pathogenic variant with ~10% GALC activity in transfected cells. There is some conflicting functional data on the proper localization of the mutant with Shin_2016 and Lim_2016 reporting proper localization while Spratley_2016 reports improper localization. Taken together, this variant is classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	One copy of this allele together with another severe allele in the homozygous state is associated with late-onset disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 31, 2019	NM_000153.3(GALC):c.1901T>C(L634S) is classified as pathogenic in the context of Krabbe disease and may be associated with a late-onset form of disease. Sources cited for classification include the following: PMID 29951496, 29966168, 30089515, 27638604, 26865610, 27126738, 24252386, 9272171, 26795590, 27780934 and 27679535. Classification of NM_000153.3(GALC):c.1901T>C(L634S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	Jan 08, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM3_VeryStrong+PP4+PS3_Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 634 of the GALC protein (p.Leu634Ser). This variant is present in population databases (rs138577661, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Krabbe disease (PMID: 9272171, 16607461, 24252386, 26865610, 27679535, 27780934). This variant is also known as Leu618Ser. ClinVar contains an entry for this variant (Variation ID: 225368). 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: 9272171, 24252386, 27126738, 27638593, 27780934). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;T;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.1

M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.5

D;D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.99

MVP

0.98

MPC

0.69

ClinPred

0.19

GERP RS

5.8

Varity_R

0.76

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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