ClinVar Genomic variation as it relates to human health
NM_018972.4(GDAP1):c.769C>T (p.Arg257Ter)
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_018972.4(GDAP1):c.769C>T (p.Arg257Ter)
Variation ID: 245608 Accession: VCV000245608.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q21.11 8: 74364059 (GRCh38) [ NCBI UCSC ] 8: 75276294 (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 Jul 25, 2016 Apr 15, 2024 Dec 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018972.4:c.769C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_061845.2:p.Arg257Ter nonsense NM_001040875.4:c.565C>T NP_001035808.1:p.Arg189Ter nonsense NM_001362929.2:c.442C>T NP_001349858.1:p.Arg148Ter nonsense NM_001362930.2:c.595C>T NP_001349859.1:p.Arg199Ter nonsense NM_001362931.2:c.694+1006C>T intron variant NM_001362932.2:c.442C>T NP_001349861.1:p.Arg148Ter nonsense NC_000008.11:g.74364059C>T NC_000008.10:g.75276294C>T NG_008787.3:g.47930C>T LRG_244:g.47930C>T LRG_244t1:c.769C>T - Protein change
- R257*, R199*, R148*, R189*
- Other names
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- Canonical SPDI
- NC_000008.11:74364058: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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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GDAP1 | - | - |
GRCh38 GRCh37 |
495 | 589 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Sep 9, 2023 | RCV000235362.16 | |
Pathogenic (2) |
criteria provided, single submitter
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- | RCV000664207.6 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 10, 2023 | RCV001206561.7 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000789164.3 |
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
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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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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease recessive intermediate A
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002072943.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The stop gained p.R257* in GDAP1 (NM_018972.4) has been reported previously in affected individuals (DiVincenzo C et al). The variant has been submitted to ClinVar … (more)
The stop gained p.R257* in GDAP1 (NM_018972.4) has been reported previously in affected individuals (DiVincenzo C et al). The variant has been submitted to ClinVar as Pathogenic. The p.R257* variant is observed in 3 individuals in gnomAD Exomes (0.001%) and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Sensory neuropathy (present)
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Likely pathogenic
(Sep 09, 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: SCV000292560.11
First in ClinVar: Jul 25, 2016 Last updated: Sep 30, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation, as the last 102 amino acids are lost, and other loss-of-function variants have been reported downstream in … (more)
Nonsense variant predicted to result in protein truncation, as the last 102 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 21322820, 31589614, 31069529, 29858556) (less)
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Pathogenic
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 4A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004037648.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: GDAP1 c.769C>T (p.Arg257X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, a commonly known mechanism for … (more)
Variant summary: GDAP1 c.769C>T (p.Arg257X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 1.2e-05 in 251470 control chromosomes (gnomAD). c.769C>T has been reported in the literature as a biallelic genotype in individuals affected with Charcot-Marie Disease Type 4A (e.g. Karakaya_2018, Ganapathy_2019). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31069529, 29858556). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 4A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001377874.3
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg257*) in the GDAP1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg257*) in the GDAP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 102 amino acid(s) of the GDAP1 protein. This variant is present in population databases (rs770501034, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive GDAP1-related conditions (PMID: 21322820). ClinVar contains an entry for this variant (Variation ID: 245608). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the GDAP1 protein in which other variant(s) (p.Phe263Leufs*22, p.Arg341Glnfs*12) have been determined to be pathogenic (PMID: 12499475, 25614874; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 2017)
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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: SCV001249599.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 25, 2018)
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no assertion criteria provided
Method: clinical testing
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Charcot-Marie-Tooth disease recessive intermediate A
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Cologne University
Accession: SCV000787765.1
First in ClinVar: Jul 28, 2018 Last updated: Jul 28, 2018 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium
Accession: SCV000928516.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
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Uncertain significance
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease type 4A
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174598.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 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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Multi-gene testing in neurological disorders showed an improved diagnostic yield: data from over 1000 Indian patients. | Ganapathy A | Journal of neurology | 2019 | PMID: 31069529 |
Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies. | Karakaya M | Human mutation | 2018 | PMID: 29858556 |
The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. | DiVincenzo C | Molecular genetics & genomic medicine | 2014 | PMID: 25614874 |
[Hereditary motor and sensory neuropathy type 4A]. | Shagina OA | Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova | 2010 | PMID: 21322820 |
Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. | Nelis E | Neurology | 2002 | PMID: 12499475 |
Text-mined citations for rs770501034 ...
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.