NM_000153.4(GALC):c.908C>T (p.Ser303Phe) AND Galactosylceramide beta-galactosidase deficiency

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Mar 29, 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:: RCV000285229.19

Allele description [Variation Report for NM_000153.4(GALC):c.908C>T (p.Ser303Phe)]

NM_000153.4(GALC):c.908C>T (p.Ser303Phe)

Gene:

GALC:galactosylceramidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q31.3

Genomic location:

Preferred name:

NM_000153.4(GALC):c.908C>T (p.Ser303Phe)

HGVS:

NC_000014.9:g.87968335G>A
NG_011853.3:g.30229C>T
NM_000153.4:c.908C>TMANE SELECT
NM_001201401.2:c.839C>T
NM_001201402.2:c.830C>T
NP_000144.2:p.Ser303Phe
NP_001188330.1:p.Ser280Phe
NP_001188331.1:p.Ser277Phe
NC_000014.8:g.88434679G>A
NG_011853.2:g.30229C>T
NM_000153.3:c.908C>T
P54803:p.Ser303Phe

Protein change:

S277F

Links:

UniProtKB: P54803#VAR_003392; dbSNP: rs756352952

NCBI 1000 Genomes Browser:

rs756352952

Molecular consequence:

NM_000153.4:c.908C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001201401.2:c.839C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001201402.2:c.830C>T - 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
SCV000389254	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (May 3, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10448809, 28598007, 9338580, 11151421, 20886637 Citation Link,
SCV000800751	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Mar 29, 2017)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20886637, 9338580, 10448809, 11151421, 21876145 Citation Link,
SCV001224311	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9338580, 11151421, 20886637, 30089515, 10448809, 28492532
SCV002093643	Natera, Inc.	no assertion criteria provided	Pathogenic (Jun 3, 2021)	germline	clinical testing
SCV002318482	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10448809, 9338580, 25741868
SCV002801173	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 10, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003922542	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 22, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20886637, 28598007, 9338580, 32912261, 11151421 Citation Link,
SCV004047462	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004807503	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2024)	germline	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	yes	1	not provided	not provided	1	not provided	clinical testing
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

Citations

PubMed

Insights into Krabbe disease from structures of galactocerebrosidase.

Deane JE, Graham SC, Kim NN, Stein PE, McNair R, Cachón-González MB, Cox TM, Read RJ.

Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15169-73. doi: 10.1073/pnas.1105639108. Epub 2011 Aug 29.

PubMed [citation]

PMID:: 21876145
PMCID:: PMC3174575

A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life.

Bascou N, DeRenzo A, Poe MD, Escolar ML.

Orphanet J Rare Dis. 2018 Aug 9;13(1):126. doi: 10.1186/s13023-018-0872-9.

PubMed [citation]

PMID:: 30089515
PMCID:: PMC6083585

See all PubMed Citations (10)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000389254.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The GALC c.908C>T (p.Ser303Phe) missense variant, also referred to as p.Ser287Phe, has been reported in at least four studies in which it is found in a total of five unrelated individuals, all affected with an infantile form of galactosylceramide beta-galactosidase deficiency disease (Krabbe disease), including in one in a homozygous state and four in a compound heterozygous state (Wenger et al. 1997; Selleri et al. 2000; Tappino et al. 2010; Zhao et al. 2017). GALC activity in patient leukocytes or fibroblasts ranged from 3 - 15% compared to control levels. All of the compound heterozygotes carried missense variants on the second allele, with one found in trans with a complex allele of two missense variants. Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The serine residue is partially conserved. Expression of the variant in COS-1 cells revealed no GALC activity in vitro (Jardim et al. 1999). Based on the evidence, the p.Ser303Phe variant is classified as 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 Counsyl, SCV000800751.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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 Invitae, SCV001224311.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 303 of the GALC protein (p.Ser303Phe). This variant is present in population databases (rs756352952, gnomAD 0.004%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 9338580, 11151421, 20886637, 30089515). This variant is also known as Ser287Phe. ClinVar contains an entry for this variant (Variation ID: 280957). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GALC function (PMID: 10448809). 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 Natera, Inc., SCV002093643.1

#	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 3billion, SCV002318482.1

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

Description

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280957, PMID:9338580). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10448809). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.957>=0.6, 3CNET: 0.946>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000284). The variant is in trans with NM_000153.4:c.136G>T variant (3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Fulgent Genetics, Fulgent Genetics, SCV002801173.1

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003922542.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: GALC c.908C>T (p.Ser303Phe) 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. Two computational tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 245686 control chromosomes (gnomAD). c.908C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Krabbe Disease, primarily with infantile onset (e.g. Wenger_1997, Selleri_2000, Tappino_2010, Zhao_2018, Krieg_2020). These data indicate that the variant is very likely to be associated with disease. Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=8)/likely pathogenic (n=2). 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 Neuberg Centre For Genomic Medicine, NCGM, SCV004047462.1

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

Description

The missense variant c.908C>T (p.Ser303Phe) in GALC gene has been reported in heterozygous state in several individuals affected with Krabbe disease (Bascou N et al.). The S303F was also reported in a patient with infantile-onset Krabbe disease who was homozygous for S303F (Wenger et al.). Experimental studies have shown that predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies (Jardim et al.). This variant has allele frequency 0.002% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The S303F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The amino acid change p.Ser303Phe in GALC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004807503.1

#	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

Last Updated: May 12, 2024

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