Variant summary: The GALC c.628A>T (p.Arg210X) variant results in a premature termination codon, predicted to cause a truncated or absent GALC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/115338 (1/57669), which does not exceed the estimated maximal expected allele frequency for a pathogenic GALC variant of 1/447. The variant of interest has been reported in an affected individual with late infantile Krabbe Disease, who was a compound heterozygote for the variant of interest. A clinical diagnostic laboratory cites the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
ClinVar Genomic variation as it relates to human health
NM_000153.4(GALC):c.628A>T (p.Arg210Ter)
Germline
Classification
Help
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.
(9)
Help
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000153.4(GALC):c.628A>T (p.Arg210Ter)
Variation ID: 369724 Accession: VCV000369724.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q31.3 14: 87976482 (GRCh38) [ NCBI UCSC ] 14: 88442826 (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 Dec 12, 2016 Oct 20, 2024 Feb 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000153.4:c.628A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000144.2:p.Arg210Ter nonsense NM_001201401.2:c.559A>T NP_001188330.1:p.Arg187Ter nonsense NM_001201402.2:c.550A>T NP_001188331.1:p.Arg184Ter nonsense NC_000014.9:g.87976482T>A NC_000014.8:g.88442826T>A NG_011853.3:g.22082A>T - Protein change
- R210*, R187*, R184*
- Other names
- -
- Canonical SPDI
- NC_000014.9:87976481:T: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.
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Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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 |
1328 | 1441 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 21, 2023 | RCV000408648.13 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000514309.18 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 27, 2022 | RCV004022127.1 |
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
(Sep 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610755.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
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Pathogenic
(Dec 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695678.1
First in ClinVar: Dec 12, 2016 Last updated: Dec 12, 2016 |
Comment:
Variant summary: The GALC c.628A>T (p.Arg210X) variant results in a premature termination codon, predicted to cause a truncated or absent GALC protein due to nonsense … (more)
Variant summary: The GALC c.628A>T (p.Arg210X) variant results in a premature termination codon, predicted to cause a truncated or absent GALC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/115338 (1/57669), which does not exceed the estimated maximal expected allele frequency for a pathogenic GALC variant of 1/447. The variant of interest has been reported in an affected individual with late infantile Krabbe Disease, who was a compound heterozygote for the variant of interest. A clinical diagnostic laboratory cites the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic." (less)
|
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Pathogenic
(Dec 15, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000484485.4
First in ClinVar: Dec 12, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 6
Sex: mixed
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Pathogenic
(Aug 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617680.4
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30777126, 22520351, 7437911, 9272171, 16607461, 31589614, 31980526) (less)
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Pathogenic
(Dec 21, 2023)
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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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000820593.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg210*) in the GALC gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg210*) in the GALC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). This variant is present in population databases (rs202131052, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with low galactocerebrosidase activity (PMID: 22520351; Invitae). This variant is also known as c.580A>T, p.Arg194*. ClinVar contains an entry for this variant (Variation ID: 369724). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 27, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004875758.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.628A>T (p.R210*) alteration, located in exon 7 (coding exon 7) of the GALC gene, consists of an A to T substitution at nucleotide position … (more)
The c.628A>T (p.R210*) alteration, located in exon 7 (coding exon 7) of the GALC gene, consists of an A to T substitution at nucleotide position 628. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 210. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation, designated as p.R194*, was identified in one individual with late onset Krabbe disease in conjunction with another GALC variant (Duffner, 2012). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Feb 01, 2024)
|
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: SCV004704324.8
First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024 |
Comment:
GALC: PVS1, PM2, PP4
Number of individuals with the variant: 1
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Likely pathogenic
(Jan 10, 2014)
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no assertion criteria provided
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132199.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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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
|
Natera, Inc.
Accession: SCV001454072.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30777126, 22520351, 7437911, 9272171, 16607461, 31589614, 31980526)
Comment:
This sequence change creates a premature translational stop signal (p.Arg210*) in the GALC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). This variant is present in population databases (rs202131052, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with low galactocerebrosidase activity (PMID: 22520351; Invitae). This variant is also known as c.580A>T, p.Arg194*. ClinVar contains an entry for this variant (Variation ID: 369724). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.628A>T (p.R210*) alteration, located in exon 7 (coding exon 7) of the GALC gene, consists of an A to T substitution at nucleotide position 628. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 210. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation, designated as p.R194*, was identified in one individual with late onset Krabbe disease in conjunction with another GALC variant (Duffner, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
GALC: PVS1, PM2, PP4
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. |
Comment:
Variant summary: The GALC c.628A>T (p.Arg210X) variant results in a premature termination codon, predicted to cause a truncated or absent GALC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/115338 (1/57669), which does not exceed the estimated maximal expected allele frequency for a pathogenic GALC variant of 1/447. The variant of interest has been reported in an affected individual with late infantile Krabbe Disease, who was a compound heterozygote for the variant of interest. A clinical diagnostic laboratory cites the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30777126, 22520351, 7437911, 9272171, 16607461, 31589614, 31980526)
Comment:
This sequence change creates a premature translational stop signal (p.Arg210*) in the GALC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). This variant is present in population databases (rs202131052, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with low galactocerebrosidase activity (PMID: 22520351; Invitae). This variant is also known as c.580A>T, p.Arg194*. ClinVar contains an entry for this variant (Variation ID: 369724). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.628A>T (p.R210*) alteration, located in exon 7 (coding exon 7) of the GALC gene, consists of an A to T substitution at nucleotide position 628. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 210. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation, designated as p.R194*, was identified in one individual with late onset Krabbe disease in conjunction with another GALC variant (Duffner, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
GALC: PVS1, PM2, PP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Later onset phenotypes of Krabbe disease: results of the world-wide registry. | Duffner PK | Pediatric neurology | 2012 | PMID: 22520351 |
| Six novel mutations detected in the GALC gene in 17 Japanese patients with Krabbe disease, and new genotype-phenotype correlation. | Xu C | Journal of human genetics | 2006 | PMID: 16607461 |
| Adult onset globoid cell leukodystrophy (Krabbe disease): analysis of galactosylceramidase cDNA from four Japanese patients. | Furuya H | Human genetics | 1997 | PMID: 9272171 |
| The Twitcher mouse: an enzymatically authentic model of human globoid cell leukodystrophy (Krabbe disease). | Kobayashi T | Brain research | 1980 | PMID: 7437911 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALC | - | - | - | - |
Text-mined citations for rs202131052 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.