ClinVar Genomic variation as it relates to human health
NM_000153.4(GALC):c.1586C>T (p.Thr529Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000153.4(GALC):c.1586C>T (p.Thr529Met)
Variation ID: 370073 Accession: VCV000370073.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q31.3 14: 87945637 (GRCh38) [ NCBI UCSC ] 14: 88411981 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 7, 2017 May 12, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000153.4:c.1586C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000144.2:p.Thr529Met missense NM_001201401.2:c.1517C>T NP_001188330.1:p.Thr506Met missense NM_001201402.2:c.1508C>T NP_001188331.1:p.Thr503Met missense NC_000014.9:g.87945637G>A NC_000014.8:g.88411981G>A NG_011853.3:g.52927C>T - Protein change
- T529M, T503M, T506M
- Other names
- -
- Canonical SPDI
- NC_000014.9:87945636:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00025
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GALC | - | - |
GRCh38 GRCh37 |
1313 | 1426 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Jan 9, 2024 | RCV000410159.22 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 10, 2022 | RCV001093133.23 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 18, 2016)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695669.1
First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894038.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163747.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Likely pathogenic
(Dec 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193824.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000153.3(GALC):c.1586C>T(T529M, aka T513M) is classified as likely pathogenic in the context of Krabbe disease. Sources cited for classification include the following: PMID 23197103, 21824559, 9266397, … (more)
NM_000153.3(GALC):c.1586C>T(T529M, aka T513M) is classified as likely pathogenic in the context of Krabbe disease. Sources cited for classification include the following: PMID 23197103, 21824559, 9266397, 9338580, 20886637 and 23128445. Classification of NM_000153.3(GALC):c.1586C>T(T529M, aka T513M) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Dec 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429611.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449967.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001554470.1
First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Family history: no
Secondary finding: no
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Pathogenic
(Apr 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512735.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4 moderate, PM2, PM3 very strong, PP1, PP3
Geographic origin: Brazil
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841401.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Functional studies provide strong evidence of the … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26865610). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.66). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000370073). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Bilateral tonic-clonic seizure with focal onset (present) , Reduced consciousness (present) , Generalized hypotonia (present)
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Pathogenic
(Mar 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021225.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000820064.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 529 of the GALC protein (p.Thr529Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 529 of the GALC protein (p.Thr529Met). This variant is present in population databases (rs200960659, gnomAD 0.02%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 9266397, 9338580, 20135576, 20886637, 21824559, 23128445, 23197103). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1538C>T (p.T513M). ClinVar contains an entry for this variant (Variation ID: 370073). 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: 26865610, 27126738). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249965.19
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454063.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951770.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964648.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV004035008.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Krabbe Disease. | Adam MP | - | 2018 | PMID: 20301416 |
Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants. | Spratley SJ | Traffic (Copenhagen, Denmark) | 2016 | PMID: 27126738 |
Altered Trafficking and Processing of GALC Mutants Correlates with Globoid Cell Leukodystrophy Severity. | Shin D | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2016 | PMID: 26865610 |
Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review. | Debs R | Journal of inherited metabolic disease | 2013 | PMID: 23197103 |
Child Neurology: Krabbe disease: a potentially treatable white matter disorder. | Gelinas J | Neurology | 2012 | PMID: 23128445 |
Early infantile Krabbe disease: results of the World-Wide Krabbe Registry. | Duffner PK | Pediatric neurology | 2011 | PMID: 21824559 |
Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease. | Tappino B | Human mutation | 2010 | PMID: 20886637 |
Intracranial calcification after cord blood neonatal transplantation for krabbe disease. | Lehman AM | Neuropediatrics | 2009 | PMID: 20135576 |
Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications. | Wenger DA | Human mutation | 1997 | PMID: 9338580 |
Prevalent mutations in the GALC gene of patients with Krabbe disease of Dutch and other European origin. | Kleijer WJ | Journal of inherited metabolic disease | 1997 | PMID: 9266397 |
Text-mined citations for rs200960659 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.