NM_000153.4(GALC):c.334A>G (p.Thr112Ala) AND not provided
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno 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
This HGVS expression did not pass validation- 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:
- 29
Condition(s)
- Synonyms:
- none provided
- Identifiers:
- MedGen: C3661900
Assertion and evidence details
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 | |
SCV000321693 | GeneDx | criteria provided, single submitter (GeneDx Variant Classification Process June 2021) | Uncertain significance (Apr 29, 2024) | germline | clinical testing | |
SCV000782710 | Mayo Clinic Laboratories, Mayo Clinic | criteria provided, single submitter (ACMG Guidelines, 2015) | Uncertain significance (May 17, 2023) | germline | clinical testing | |
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 | |
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 | |
SCV001553663 | Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)
| 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
| 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
| 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
| 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 |
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.
- PMID:
- 23197103
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.
- PMID:
- 24388568
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