NM_000153.4(GALC):c.1901T>C (p.Leu634Ser) AND Galactosylceramide beta-galactosidase deficiency

Germline classification:: Pathogenic/Likely pathogenic (11 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000345880.28

Allele description [Variation Report for NM_000153.4(GALC):c.1901T>C (p.Leu634Ser)]

NM_000153.4(GALC):c.1901T>C (p.Leu634Ser)

Gene:

GALC:galactosylceramidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q31.3

Genomic location:

Preferred name:

NM_000153.4(GALC):c.1901T>C (p.Leu634Ser)

HGVS:

NC_000014.9:g.87939915A>G
NG_011853.3:g.58649T>C
NM_000153.4:c.1901T>CMANE SELECT
NM_001201401.2:c.1832T>C
NM_001201402.2:c.1823T>C
NP_000144.2:p.Leu634Ser
NP_001188330.1:p.Leu611Ser
NP_001188331.1:p.Leu608Ser
NC_000014.8:g.88406259A>G
NG_011853.2:g.58649T>C
NM_000153.3:c.1901T>C
P54803:p.Leu634Ser

Protein change:

L608S

Links:

UniProtKB: P54803#VAR_013968; dbSNP: rs138577661

NCBI 1000 Genomes Browser:

rs138577661

Molecular consequence:

NM_000153.4:c.1901T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001201401.2:c.1832T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001201402.2:c.1823T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Galactosylceramide beta-galactosidase deficiency
Synonyms:: Krabbe leukodystrophy; Globoid cell leukoencephalopathy; Galactocerebrosidase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009499; MedGen: C0023521; Orphanet: 487; OMIM: 245200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000267329	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 18, 2016)	germline	reference population	PubMed (3) [See all records that cite these PMIDs] 24252386, 9272171, 25741868
SCV000389235	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Apr 5, 2019)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 26865610, 9272171, 9371928, 16607461, 24252386, 27126738, 26795590, 27780934, 27679535 Citation Link,
SCV000695674	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 12, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24252386, 9272171, 16607461, 26795590 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000835189	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16607461, 26865610, 27679535, 9272171, 24252386, 27126738, 27638593, 27780934, 28492532
SCV001163745	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193893	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 31, 2019)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 29951496, 29966168, 30089515, 27638604, 26865610, 27126738, 24252386, 9272171, 26795590, 27780934, 27679535 Citation Link,
SCV001464120	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001810430	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002580670	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004035010	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 24252386, 29951496

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
East Asian	germline	unknown	1	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

Adult-onset Krabbe disease with homozygous T1853C mutation in the galactocerebrosidase gene. Unusual MRI findings of corticospinal tract demyelination.

Satoh JI, Tokumoto H, Kurohara K, Yukitake M, Matsui M, Kuroda Y, Yamamoto T, Furuya H, Shinnoh N, Kobayashi T, Kukita Y, Hayashi K.

Neurology. 1997 Nov;49(5):1392-9. Review.

PubMed [citation]

PMID:: 9371928

Six novel mutations detected in the GALC gene in 17 Japanese patients with Krabbe disease, and new genotype-phenotype correlation.

Xu C, Sakai N, Taniike M, Inui K, Ozono K.

J Hum Genet. 2006;51(6):548-554. doi: 10.1007/s10038-006-0396-3. Epub 2006 Apr 11.

PubMed [citation]

PMID:: 16607461

See all PubMed Citations (16)

Details of each submission

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267329.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	1	not provided	not provided	reference population	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000389235.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695674.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000835189.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163745.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Molecular Medicine, Children’s Hospital of Fudan University, SCV001190543.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193893.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001464120.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001810430.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002580670.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From GeneReviews, SCV004035010.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

One copy of this allele together with another severe allele in the homozygous state is associated with late-onset disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001190543	Center for Molecular Medicine, Children’s Hospital of Fudan University	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Benign (May 10, 2019)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001190543

Center for Molecular Medicine, Children’s Hospital of Fudan University

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Benign
(May 10, 2019)

paternal

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: May 7, 2024

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