ClinVar Genomic variation as it relates to human health
NM_000153.4(GALC):c.2041G>A (p.Val681Met)
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.
Pathogenic(2); Likely pathogenic(3); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000153.4(GALC):c.2041G>A (p.Val681Met)
Variation ID: 208291 Accession: VCV000208291.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q31.3 14: 87934749 (GRCh38) [ NCBI UCSC ] 14: 88401093 (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 Feb 2, 2016 Apr 15, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000153.4:c.2041G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000144.2:p.Val681Met missense NM_001201401.2:c.1972G>A NP_001188330.1:p.Val658Met missense NM_001201402.2:c.1963G>A NP_001188331.1:p.Val655Met missense NC_000014.9:g.87934749C>T NC_000014.8:g.88401093C>T NG_011853.3:g.63815G>A P54803:p.Val681Met - Protein change
- V681M, V655M, V658M
- Other names
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- Canonical SPDI
- NC_000014.9:87934748:C:T
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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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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
1000 Genomes Project 30x 0.00016
Exome Aggregation Consortium (ExAC) 0.00017
The Genome Aggregation Database (gnomAD), exomes 0.00019
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 |
1307 | 1420 |
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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000206966.8 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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May 11, 2023 | RCV001093132.21 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 10, 2023 | RCV001824669.3 |
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
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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
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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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Likely pathogenic
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267330.1
First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Likely 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: SCV001163744.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Pathogenic
(Feb 24, 2022)
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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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MGZ Medical Genetics Center
Accession: SCV002579765.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 6
Sex: female
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Uncertain significance
(May 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074500.2
First in ClinVar: Feb 12, 2022 Last updated: Jun 24, 2023 |
Comment:
Variant summary: GALC c.2041G>A (p.Val681Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: GALC c.2041G>A (p.Val681Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 248920 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GALC causing Krabbe Disease (0.00019 vs 0.0022), allowing no conclusion about variant significance. c.2041G>A has been reported in the literature as a compound heterozygous genotype in two individuals affected with adult onset presentations of Krabbe Disease (example, Yang_2013, Xie_2020) and one case of Krabbe Diasese diagnosed at newborn screening (Li_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Saavendra-Matiz_2016). These results showed no damaging effect of this variant in isolation but when associated in cis with a different variant, namely p.I546T, a "haplotype effect" was observed such that the construct bearing p.V665M+p.I546T in cis demonstrated GALC enzyme activity of approximately 30% of normal WT levels. This variant is characterized as a mild allele when in cis with p.I546T. Lastly, the presence of this co-occurring allele in the three ascertained cases mentioned above cannot be unequivocally ruled out. The following publications have been ascertained in the context of this evaluation (PMID: 35419325, 27638593, 31885218, 23462331). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=4) and VUS (n=1). Based on the evidence outlined above, the variant in isolation was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(May 11, 2023)
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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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GeneDx
Accession: SCV004168111.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
The significance of this variant, alone or in cis with another variant is not clear at present (PMID: 27638593); In silico analysis supports that this … (more)
The significance of this variant, alone or in cis with another variant is not clear at present (PMID: 27638593); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(V665M); This variant is associated with the following publications: (PMID: 34426522, 31589614, 36161165, 36341094, 23462331, 31885218, 35419325, 27638593) (less)
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Uncertain significance
(Nov 16, 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: SCV003808553.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 17, 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: SCV002240802.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 681 of the GALC protein (p.Val681Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 681 of the GALC protein (p.Val681Met). This variant is present in population databases (rs200607029, gnomAD 0.1%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 23462331, 31885218). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208291). 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 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249964.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Jun 27, 2013)
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no assertion criteria provided
Method: literature only
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Galactosylceramide beta-galactosidase deficiency
Affected status: yes
Allele origin:
germline
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000244018.1
First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016 |
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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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Establishment of Cutoff Values for Newborn Screening of Six Lysosomal Storage Disorders by Tandem Mass Spectrometry. | Li R | Frontiers in pediatrics | 2022 | PMID: 35419325 |
New clinical characteristics and novel pathogenic variants of patients with hereditary leukodystrophies. | Xie JJ | CNS neuroscience & therapeutics | 2020 | PMID: 31885218 |
Expression of individual mutations and haplotypes in the galactocerebrosidase gene identified by the newborn screening program in New York State and in confirmed cases of Krabbe's disease. | Saavedra-Matiz CA | Journal of neuroscience research | 2016 | PMID: 27638593 |
Four novel GALC gene mutations in two Chinese patients with Krabbe disease. | Yang Y | Gene | 2013 | PMID: 23462331 |
http://web.expasy.org/variant_pages/VAR_069512.html | - | - | - | - |
Text-mined citations for rs200607029 ...
HelpRecord last updated Apr 15, 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.