NM_000153.4(GALC):c.334A>G (p.Thr112Ala) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (11 submissions)
Last evaluated:: May 1, 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:: RCV000790805.46

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000230033	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Uncertain significance (Jan 5, 2017)	germline	clinical testing	Citation Link,
SCV000321693	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 29, 2024)	germline	clinical testing	Citation Link,
SCV000782710	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 17, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 23197103, 24388568, 26915362, 27638592, 27638593, 29481565, 31053700, 34065072, 34449528, 8687180, 25741868
SCV001149290	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (May 1, 2024)	germline	clinical testing	Citation Link,
SCV001447103	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001553663	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Likely pathogenic	unknown	clinical testing
SCV001744902	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001921650	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001959925	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001963728	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV003816306	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 22, 2023)	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	unknown	18	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	11	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review.

Debs R, Froissart R, Aubourg P, Papeix C, Douillard C, Degos B, Fontaine B, Audoin B, Lacour A, Said G, Vanier MT, Sedel F.

J Inherit Metab Dis. 2013 Sep;36(5):859-68. doi: 10.1007/s10545-012-9560-4. Epub 2012 Nov 30.

PubMed [citation]

PMID:: 23197103

Krabbe disease: are certain mutations disease-causing only when specific polymorphisms are present or when inherited in trans with specific second mutations?

Wenger DA, Luzi P, Rafi MA.

Mol Genet Metab. 2014 Mar;111(3):307-308. doi: 10.1016/j.ymgme.2013.12.009. Epub 2013 Dec 19. No abstract available.

PubMed [citation]

PMID:: 24388568

See all PubMed Citations (11)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000230033.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	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		11	not provided	not provided	not provided

From GeneDx, SCV000321693.9

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

Description

Reported previously in association with later-onset Krabbe disease in two individuals, one of whom had 5 additional coding variants in GALC and the second had 2 additional coding variants, the phase of the other variants in these cases was unknown (PMID: 8687180, 23197103); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27276562, 24082139, 23891399, 27533158, 30609409, 23197103, 27638593, 23509109, 30202406, 31664448, 29481565, 31053700, 24388568, 26915362, 34426522, 32860008, 34065072, 31980526, 8687180, 26795590, 33742171, 36964991, 36781956, 34531397, 32483926, 31847883)

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV000782710.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (11)

Description

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		7	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001149290.27

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

Description

GALC: PS3:Moderate, PP3

#	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		11	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447103.1

#	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	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553663.1

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

Description

The GALC p.T112A variant was identified in 106 of 1306 proband chromosomes (frequency: 0.08) from individuals with late-onset Krabbe disease (Orsini_2016_PMID:26795590; Debs_2013_PMID:23197103). This variant was also found to segregate with disease in one family with late-onset Krabbe disease with predominant cerebellar ataxia in five affected individuals, all of whom were compound heterozygous for the GALC p.T112A and p.E198K variants (Shao_2016_PMID:26915362). In many cases, the p.T112A variant is also found in cis with another GALC variant, such as the p.I1546T variant (Luiz_1996_PMID:8687180; Orsini_2016_PMID:26795590). The variant was identified in dbSNP (ID: rs147313927) and ClinVar (classified as uncertain significance by GeneDx, EGL Genetic Diagnostics, Invitae and Mayo Clinic, as likely pathogenic by Laboratory for Molecular Medicine and as likely benign by Mendelics). The variant was identified in control databases in 709 of 280348 chromosomes (4 homozygous) at a frequency of 0.002529 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 516 of 128292 chromosomes (freq: 0.004022), European (Finnish) in 65 of 25000 chromosomes (freq: 0.0026), South Asian in 60 of 30568 chromosomes (freq: 0.001963), Other in 14 of 7138 chromosomes (freq: 0.001961), Latino in 34 of 35290 chromosomes (freq: 0.000963), African in 18 of 24176 chromosomes (freq: 0.000745), Ashkenazi Jewish in 1 of 10352 chromosomes (freq: 0.000097), and East Asian in 1 of 19532 chromosomes (freq: 0.000051). The p.T112 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. A functional GALC expression study conducted on this variant using COS1 cells found reduced GALC activity compared to the wild type, with GALC activity even more significantly reduced when another GALC variant is present with the p.T112A variant (Saavedra-Matiz_2016_PMID:27638593). In summary, this variant is considered a hypomorphic allele which, in combination with other variants in cis or trans, may result in reduced activity. Based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

#	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 Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001744902.3

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

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001921650.1

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001959925.1

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001963728.1

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

From Revvity Omics, Revvity, SCV003816306.2

#	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: Oct 26, 2024

Relating variation to medicine