NM_000153.4(GALC):c.749T>C (p.Ile250Thr) AND Galactosylceramide beta-galactosidase deficiency

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jan 8, 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:: RCV000984177.12

Allele description [Variation Report for NM_000153.4(GALC):c.749T>C (p.Ile250Thr)]

NM_000153.4(GALC):c.749T>C (p.Ile250Thr)

Gene:

GALC:galactosylceramidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q31.3

Genomic location:

Preferred name:

NM_000153.4(GALC):c.749T>C (p.Ile250Thr)

HGVS:

NC_000014.9:g.87976361A>G
NG_011853.3:g.22203T>C
NM_000153.4:c.749T>CMANE SELECT
NM_001201401.2:c.680T>C
NM_001201402.2:c.671T>C
NP_000144.2:p.Ile250Thr
NP_001188330.1:p.Ile227Thr
NP_001188331.1:p.Ile224Thr
NC_000014.8:g.88442705A>G
NG_011853.2:g.22203T>C
NM_000153.3:c.749T>C
P54803:p.Ile250Thr

Protein change:

I224T

Links:

UniProtKB: P54803#VAR_003387; dbSNP: rs886039569

NCBI 1000 Genomes Browser:

rs886039569

Molecular consequence:

NM_000153.4:c.749T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001201401.2:c.680T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001201402.2:c.671T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001132201	Counsyl	no assertion criteria provided	Pathogenic (Nov 16, 2016)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20410102, 9338580, 27442402, 20886637, 26108647, 16607461, 8940268
SCV001251627	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Feb 13, 2020)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26108647, 20410102, 8940268 Citation Link,
SCV001370000	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001454070	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001976851	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 5, 2021)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002246695	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27442402, 8940268, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications.

Wenger DA, Rafi MA, Luzi P.

Hum Mutat. 1997;10(4):268-79. Review.

PubMed [citation]

PMID:: 9338580

Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease.

Tappino B, Biancheri R, Mort M, Regis S, Corsolini F, Rossi A, Stroppiano M, Lualdi S, Fiumara A, Bembi B, Di Rocco M, Cooper DN, Filocamo M.

Hum Mutat. 2010 Dec;31(12):E1894-914. doi: 10.1002/humu.21367.

PubMed [citation]

PMID:: 20886637
PMCID:: PMC3052420

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV001132201.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	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 Illumina Laboratory Services, Illumina, SCV001251627.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The GALC c.749T>C (p.Ile250Thr) variant is a missense variant that has been recognized as a common variant in individuals with Krabbe disease who are of Greek ancestry. Across a selection of the available literature, this variant, which was previously referred to as p.Ile234Thr, has been reported in a homozygous state in at least four unrelated individuals and in a compound heterozygous state in two individuals (De Gasperi et al. 1996; Dimitriou et al. 2016). The variant also segregated with the disease in one additional affected individual. Age of onset was in the neonatal period or first few years of life. Functional studies in COS cells and in the human CNS-derived cell line H4 demonstrated negligible residual enzyme activity compared to WT as well as disrupted precursor processing (De Gasperi et al. 1996; Lee et al. 2010). Based on the collective evidence, the p.Ile250Thr variant is classified as pathogenic for Krabbe disease.

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001370000.2

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

Description

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3.

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

From Natera, Inc., SCV001454070.1

#	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 Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV001976851.1

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

Description

PM2, PP2, PP3, PM3, PP5

#	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 Invitae, SCV002246695.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 250 of the GALC protein (p.Ile250Thr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 8940268, 27442402). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.701T>C (p.I234T). ClinVar contains an entry for this variant (Variation ID: 265479). 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: 8940268). 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

Last Updated: Mar 16, 2024

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