ClinVar Genomic variation as it relates to human health
NM_000153.4(GALC):c.195G>C (p.Gly65=)
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.195G>C (p.Gly65=)
Variation ID: 280959 Accession: VCV000280959.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q31.3 14: 87992970 (GRCh38) [ NCBI UCSC ] 14: 88459314 (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 6, 2016 Feb 14, 2024 Dec 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000153.4:c.195G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000144.2:p.Gly65= synonymous NM_001201401.2:c.195G>C NP_001188330.1:p.Gly65= synonymous NM_001201402.2:c.117+413G>C intron variant NC_000014.9:g.87992970C>G NC_000014.8:g.88459314C>G NG_011853.3:g.5594G>C - Protein change
- Other names
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- Canonical SPDI
- NC_000014.9:87992969:C:G
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00012
1000 Genomes Project 30x 0.00016
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
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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 |
1312 | 1425 | |
LOC130056217 | - | - | - | GRCh38 | - | 87 |
Conditions - Germline
Condition
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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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Dec 2, 2023 | RCV000400667.9 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2017 | RCV000513714.6 |
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
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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
(May 18, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000330946.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Sep 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610708.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
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Likely pathogenic
(Apr 26, 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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Counsyl
Accession: SCV000799504.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(Mar 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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KRABBE DISEASE
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001443768.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
This variant affects the splice donor site of exon 1 and is therefore predicted to interfere with splicing and result in loss of normal protein … (more)
This variant affects the splice donor site of exon 1 and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has been previously reported in individuals with late onset Krabbe's disease as a compound heterozygous change in two related individuals (PMID: 9005874, 8940268), the compound homozygous state in one individual (PMID: 23197103), and in one individual with no second variant identified (PMID: 23197103). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (2/31320) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. This variant is present in the ClinVar database (Variation ID: 280959). Functional studies support a damaging effect of this variant on splicing (PMID: 8940268). . Based on the available evidence, the c.195G>C (p.Gly65=) variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 18, 2022)
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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: SCV002819635.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: GALC c.195G>C (p.Gly65Gly) alters a conserved nucleotide located as the last nucleotide of exon 1 adjacent to the canonical intron 1 splice donor … (more)
Variant summary: GALC c.195G>C (p.Gly65Gly) alters a conserved nucleotide located as the last nucleotide of exon 1 adjacent to the canonical intron 1 splice donor site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in first 126 bases of intron 1 inserted in-frame between nucleotides 195 and 196 (legacy nucleotides 147 and 148) (exactly at the junction of exons 1 and 2), because of the activation of a cryptic splice site (De Gasperi_1996). The variant was absent in 125252 control chromosomes. c.195G>C has been reported in the literature in individuals affected with slowly progressive/late onset Krabbe Disease (example, De Gasperi_1996, Bernardini_1997, Debs_2013). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 02, 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
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Invitae
Accession: SCV000964060.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects codon 65 of the GALC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 65 of the GALC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GALC protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has been observed in individual(s) with Krabbe disease (PMID: 8940268, 9005874, 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. ClinVar contains an entry for this variant (Variation ID: 280959). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in abnormal splicing and introduces a premature termination codon (PMID: 8940268). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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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 in the Arab World. | Zayed H | Journal of pediatric genetics | 2015 | PMID: 27617109 |
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 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Adult-onset Krabbe's disease in siblings with novel mutations in the galactocerebrosidase gene. | Bernardini GL | Annals of neurology | 1997 | PMID: 9005874 |
Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy. | De Gasperi R | American journal of human genetics | 1996 | PMID: 8940268 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALC | - | - | - | - |
Text-mined citations for rs886042057 ...
HelpRecord last updated Feb 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.