NM_000153.4(GALC):c.334A>G (p.Thr112Ala) AND Galactosylceramide beta-galactosidase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (14 submissions)
Last evaluated:: May 9, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000178047.38

Allele description [Variation Report for NM_000153.4(GALC):c.334A>G (p.Thr112Ala)]

NM_000153.4(GALC):c.334A>G (p.Thr112Ala)

Gene:

GALC:galactosylceramidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q31.3

Genomic location:

Preferred name:

NM_000153.4(GALC):c.334A>G (p.Thr112Ala)

HGVS:

NC_000014.9:g.87986597T>C
NG_011853.3:g.11967A>G
NM_000153.4:c.334A>GMANE SELECT
NM_001201401.2:c.265A>G
NM_001201402.2:c.256A>G
NP_000144.2:p.Thr112Ala
NP_000144.2:p.Thr112Ala
NP_001188330.1:p.Thr89Ala
NP_001188331.1:p.Thr86Ala
NC_000014.8:g.88452941T>C
NG_011853.2:g.11967A>G
NM_000153.3:c.334A>G
P54803:p.Thr112Ala

Protein change:

T112A

Links:

UniProtKB: P54803#VAR_003382; dbSNP: rs147313927

NCBI 1000 Genomes Browser:

rs147313927

Molecular consequence:

NM_000153.4:c.334A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001201401.2:c.265A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001201402.2:c.256A>G - 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

Recent activity

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MULTISPECIES: chloramphenicol efflux MFS transporter CmlA4 [Gammaproteobacteria]
MULTISPECIES: chloramphenicol efflux MFS transporter CmlA4 [Gammaproteobacteria]
gi|644808165|ref|WP_025368619.1|

Protein
cytochrome b, partial (mitochondrion) [Cinara pilicornis]
cytochrome b, partial (mitochondrion) [Cinara pilicornis]
gi|635263288|gb|AHZ66423.1|

Protein
cytochrome b, partial (mitochondrion) [Cinara ponderosae]
cytochrome b, partial (mitochondrion) [Cinara ponderosae]
gi|635263266|gb|AHZ66412.1|

Protein
cytochrome b, partial (mitochondrion) [Cinara pinimaritimae]
cytochrome b, partial (mitochondrion) [Cinara pinimaritimae]
gi|635263292|gb|AHZ66425.1|

Protein
zinc finger MYM-type protein 1 isoform X8 [Homo sapiens]
zinc finger MYM-type protein 1 isoform X8 [Homo sapiens]
gi|2462513724|ref|XP_054194772.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000731413	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 18, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8687180, 26915362, 23197103, 27638593, 26795590, 23509109, 25741868
SCV000832108	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 31, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23197103, 26915362, 26795590, 27638593, 28492532
SCV001139498	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Dec 26, 2023)	unknown	clinical testing	Citation Link,
SCV001251628	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (Feb 13, 2020)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 29481565, 31053700, 23197103, 26795590, 27638593, 26915362, 8687180 Citation Link,
SCV001426472	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32860008
SCV001440770	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002093654	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jan 9, 2020)	germline	clinical testing
SCV002499666	Institute of Human Genetics, University Hospital Muenster	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002503750	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 20, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8687180, 21876145, 23197103, 26795590, 26915362, 27638593, 31053700, 25741868
SCV002580936	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002767725	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 21, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26795590, 26915362, 27638593, 31053700, 25741868
SCV004025899	Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004035014	GeneReviews	no classification provided	not provided	germline	literature only
SCV005043137	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 9, 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	5	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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cost-effective and scalable DNA extraction method from dried blood spots.

Saavedra-Matiz CA, Isabelle JT, Biski CK, Duva SJ, Sweeney ML, Parker AL, Young AJ, Diantonio LL, Krein LM, Nichols MJ, Caggana M.

Clin Chem. 2013 Jul;59(7):1045-51. doi: 10.1373/clinchem.2012.198945. Epub 2013 Mar 18.

PubMed [citation]

PMID:: 23509109

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (12)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731413.2

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

Description

The p.Thr112Ala (NM_000153.3 c.334A>G, also referred to as p.Thr96Ala) variant in GALC has been reported in 4 compound heterozygous individuals with clinical features of late-onset Krabbe disease (Luzi 1996 PMID: 8687180, Debs 2013 PMID: 23197103, and Shao 2016 PMID: 26915362), and segregated in 3 affected siblings (Shao 2016 PMID: 26915362). This variant is also the most common referral for followup testing for Krabbe disease by newborn screening programs in the heterozygous, homozygous, and compound heterozygous states (Orsini 2016 PMID: 26795590). Upon further testing, these newborns were all classified into the moderate-, low-, or no-risk categories. This variant has been identified in 0.4% (508/126254) of European chromosomes and 4 homozygotes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs147313927). This variant has also been reported in ClinVar (Variation ID 92503). In vitro functional studies provide evidence that the p.Thr112Ala variant leads to reduced enzymatic activity, though not at levels as low as variants causing infantile-onset disease (Saavedra-Matiz 2016 PMID: 23509109, Orsini 2016 PMID: 26795590). Computational prediction tools and conservation analysis suggest that the p.Thr112Ala variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain and although at least one individual affected during childhood has been reported, has typically been associated with late-onset disease. ACMG/AMP Criteria applied: BS1, PS3_Moderate, PM3, PP1, PP3.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000832108.5

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

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 112 of the GALC protein (p.Thr112Ala). This variant is present in population databases (rs147313927, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This variant has been reported in combination with other GALC variants in individuals affected with late-onset Krabbe disease with evidence of disease co-segregation in one family (PMID: 23197103, 26915362). This variant is also one of the most common variants that is detected in newborns who are referred for low galactocerebrosidase activity on newborn screening, but interestingly, none of the newborns were categorized as high risk for Krabbe disease (PMID: 26795590). One study has suggested that the p.Thr112Ala variant may become a disease-associated allele only when it co-occurs on the same chromosome (in cis) with the p.Ile562Thr polymorphism (PMID: 27638593). However, the evidence is not sufficient to support a pathogenic haplotype at this time. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92503). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GALC protein function. Experimental studies have shown that this missense change alone causes a mild reduction of GALC enzyme activity in vitro and the effect is exacerbated in the presence of other GALC variants in cis (PMID: 27638593). In summary, while this variant has been reported in individuals with Krabbe disease in the literature, there are multiple homozygous individuals observed in population databases. In addition, clinical and experimental data suggest that co-occurrence in cis with other GALC variant(s) may be required for this variant to be disease-causing (PMID: 27638593). The available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Mendelics, SCV001139498.2

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

From Illumina Laboratory Services, Illumina, SCV001251628.2

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

Description

The GALC c.334A>G (p.Thr112Ala) variant, which was previously referred to as p.Thr96Ala, is a missense variant that has been reported in association with Krabbe disease in several studies. Shao et al. (2016) reported the variant in five members of a French-Canadian family who all presented with adult-onset disease with predominant cerebellar ataxia and mild spasticity. Nashabat et al. (2019) described a 6-year-old female with early-onset Krabbe disease who was homozygous for the p.Thr112Ala variant and showed low galactocerebrosidase enzyme activity in cultured fibroblasts but normal levels in peripheral blood. This variant was also found to be enriched among infants with GALC activity <12% of normal who were identified through newborn screening (Orsini et al. 2016) and has also been reported in a compound heterozygous state in several affected individuals who were also heterozygous for common enzyme activity-lowering variants, including p.Ile562Thr (previously p.Ile546Thr) (Luzi et al. 1996; Debs et al. 2013). Notably, this variant is reported at a frequency of 0.004022 in the European (non-Finnish) population of the Genome Aggregation Database, which also includes four homozygous carriers. Functional studies in COS1 cells showed the p.Thr112Ala-containing enzyme showed approximately 30% of wild type activity; residual activity was even lower when an additional pseudodeficiency variant was co-expressed (Luzi et al. 1996; Saavedra-Matiz et al. 2016). Marshall et al. (2018) asserted that the p.Thr112Ala variant should be considered a disease-causing allele when in cis with a common enzyme activity reducing variant or when in trans with a severe allele. Based on the collective evidence and application of the ACMG criteria, the p.Thr112Ala variant is classified as likely 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 Centogene AG - the Rare Disease Company, SCV001426472.1

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

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001440770.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002093654.1

#	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 Institute of Human Genetics, University Hospital Muenster, SCV002499666.1

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

Description

ACMG categories: PS3,PM1,PM3,PP3

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

From Molecular Genetics, Royal Melbourne Hospital, SCV002503750.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change is predicted to replace threonine with alanine at codon 112 of the GALC protein (p.(Thr112Ala), also known as p.Thr96Ala). The threonine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the Glycosyl hydrolase family 59 domain in a triosephosphate isomerase barrel (PMID: 21876145). There is a small physicochemical difference between threonine and alanine. The variant is present in a large population cohort at a frequency of 0.25% (rs147313927, 709/280,348 alleles, 4 homozygotes in gnomAD v2.1), with an allele frequency of 0.4% in the European (non-Finnish) population (BS1; gnomAD v2.1). The variant has been identified in the homozygous state and compound heterozygous with a second allele in at least three individuals with Krabbe disease, and reported to segregate with adult-onset predominant cerebellar ataxia with mild spasticity in five affected individuals (PP1_Strong, PM3; PMID: 8687180, 23197103, 26915362, 31053700). The variant has been reported with reduced enzyme activity in patient cells and in in vitro assays. However, there is in vitro and patient enzyme activity evidence that occurrence of the pseudoefficiency variant p.Ile562Thr is required in cis with the variant to produce disease causing GALC deficiency (PMID: 8687180, 26795590, 27638593). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 5/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP1_Strong, PM3, BS1, PP3.

#	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 MGZ Medical Genetics Center, SCV002580936.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767725.1

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

Description

A homozygous missense variant was identified, NM_000153.3(GALC):c.334A>G in exon 4 of the GALC gene. This substitution is predicted to create a minor amino acid change from a threonine to an alanine at position 112 of the protein; NP_000144.2(GALC):p.Thr112Ala. The threonine at this position has very high conservation (100 vertebrates, UCSC), and is located within the Glycosyl hydrolase family 59 functional domain (NCBI, PDB). In silico software predicts this variant to be damaging (PolyPhen2, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a global population frequency of 0.25% (701 heterozygotes, 4 homozygotes) with a European sub-population frequency of 0.40%. This variant has been previously reported as likely pathogenic in patients with Krabbe disease (Nashabat, M., et al. (2019)), and as a VUS (ClinVar, Orsini, J. J., et al. (2016)). It has also been shown to segregate with disease in one family (Shao, Y. H. et al. (2016)). In addition, functional studies show reduced GALC activity but the effect of this reduction is unknown (Orsini, J. J., et al. (2016), Saavedra-Matiz, C. A. et al. (2016)). Based on information available at the time of curation, this variant has been classified as a VUS.

#	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 Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital, SCV004025899.1

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

From GeneReviews, SCV004035014.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV005043137.1

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

Description

A heterozygous variant in exon 4 of the GALC gene that results in the amino acid substitution of Alanine for Threonine at codon 112 was detected. The observed variant c.334A>G (p.Thr112Ala) has not been reported in the 1000 genomes database and has MAF of 0.2526% in gnomAD database. The in silico prediction is damaging by MutationTaster and DANN. In summary, the variant meets our criteria to be classified as likely 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		1	not provided	not provided	not provided

Last Updated: Oct 26, 2024

Relating variation to medicine