NM_000153.4(GALC):c.1657G>A (p.Gly553Arg) AND Galactosylceramide beta-galactosidase deficiency

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Nov 5, 2023
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:: RCV000169525.12

Allele description [Variation Report for NM_000153.4(GALC):c.1657G>A (p.Gly553Arg)]

NM_000153.4(GALC):c.1657G>A (p.Gly553Arg)

Gene:

GALC:galactosylceramidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q31.3

Genomic location:

Preferred name:

NM_000153.4(GALC):c.1657G>A (p.Gly553Arg)

HGVS:

NC_000014.9:g.87945566C>T
NG_011853.3:g.52998G>A
NM_000153.4:c.1657G>AMANE SELECT
NM_001201401.2:c.1588G>A
NM_001201402.2:c.1579G>A
NP_000144.2:p.Gly553Arg
NP_001188330.1:p.Gly530Arg
NP_001188331.1:p.Gly527Arg
NC_000014.8:g.88411910C>T
NG_011853.2:g.52998G>A
NM_000153.3:c.1657G>A
P54803:p.Gly553Arg

Protein change:

G527R; GLY553ARG

Links:

UniProtKB: P54803#VAR_013967; OMIM: 606890.0005; dbSNP: rs748573754

NCBI 1000 Genomes Browser:

rs748573754

Molecular consequence:

NM_000153.4:c.1657G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001201401.2:c.1588G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001201402.2:c.1579G>A - 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
SCV000044881	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2010)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000221002	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Dec 31, 2014)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 24913062, 23138179, 20886637, 10477434 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001203582	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 5, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20886637, 10477434, 27638593, 28492532
SCV001442678	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 2, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20886637, 27638593, 10477434 Citation Link,
SCV001454062	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002792287	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 8, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	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, literature only

Citations

PubMed

Pharmacological chaperones increase residual β-galactocerebrosidase activity in fibroblasts from Krabbe patients.

Berardi AS, Pannuzzo G, Graziano A, Costantino-Ceccarini E, Piomboni P, Luddi A.

Mol Genet Metab. 2014 Aug;112(4):294-301. doi: 10.1016/j.ymgme.2014.05.009. Epub 2014 May 23.

PubMed [citation]

PMID:: 24913062

A high-throughput screening assay using Krabbe disease patient cells.

Ribbens J, Whiteley G, Furuya H, Southall N, Hu X, Marugan J, Ferrer M, Maegawa GH.

Anal Biochem. 2013 Mar 1;434(1):15-25. doi: 10.1016/j.ab.2012.10.034. Epub 2012 Nov 5.

PubMed [citation]

PMID:: 23138179
PMCID:: PMC3975245

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000044881.2

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

Description

In patients with Krabbe disease (KRB; 245200), Tappino et al. (2010) identified a 1657G-A transition in exon 14 of the GALC gene, resulting in a gly553-to-arg (G553R) substitution. The G553R mutation was found in 7 Italian patients from southern Italy, and haplotype analysis indicated a founder effect.

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

From Counsyl, SCV000221002.2

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001203582.5

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 553 of the GALC protein (p.Gly553Arg). This variant is present in population databases (rs748573754, gnomAD 0.002%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 10477434, 20886637). This variant is also known as c.1609G>A (p.Gly537Arg). ClinVar contains an entry for this variant (Variation ID: 189113). 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: 10477434, 27638593). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442678.1

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

Description

Variant summary: GALC c.1657G>A (p.Gly553Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248898 control chromosomes. c.1657G>A has been reported in the literature in multiple individuals affected with Krabbe Disease (example, DeGasperi_1999, Tappino_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal GALC activity in an in-vitro assay (De Gasperi_1999). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Natera, Inc., SCV001454062.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002792287.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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