ClinVar Genomic variation as it relates to human health
NM_000166.6(GJB1):c.614A>G (p.Asn205Ser)
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_000166.6(GJB1):c.614A>G (p.Asn205Ser)
Variation ID: 10442 Accession: VCV000010442.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq13.1 X: 71224321 (GRCh38) [ NCBI UCSC ] X: 70444171 (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 Apr 4, 2013 Oct 8, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000166.6:c.614A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000157.1:p.Asn205Ser missense NM_001097642.3:c.614A>G NP_001091111.1:p.Asn205Ser missense NC_000023.11:g.71224321A>G NC_000023.10:g.70444171A>G NG_008357.1:g.14110A>G LRG_245:g.14110A>G LRG_245t2:c.614A>G LRG_245p2:p.Asn205Ser P08034:p.Asn205Ser - Protein change
- N205S
- Other names
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- Canonical SPDI
- NC_000023.11:71224320:A: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.
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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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GJB1 | - | - |
GRCh38 GRCh37 |
793 | 924 |
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
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 (2) |
no assertion criteria provided
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Feb 1, 1999 | RCV000011187.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2024 | RCV000537008.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2023 | RCV000991856.23 |
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
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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
(Aug 15, 2019)
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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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Athena Diagnostics
Accession: SCV001143682.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/201577 chr). Statistically enriched in patients compared to ethnically matched controls. Found … (more)
Not found in the total gnomAD dataset, and the data is high quality (0/201577 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. The gain of a new splice site is predicted. Results on protein functions were conflicting. Moderate co-segregation with disease in affected individuals from a single family. (less)
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Pathogenic
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth Neuropathy X
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000658918.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 205 of the GJB1 protein (p.Asn205Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 205 of the GJB1 protein (p.Asn205Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked Charcot-Marie-Tooth disease (CMTX) (PMID: 9401007, 9452099, 10071100, 12497641, 19259128, 24327141, 27544631, 28469099). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10442). 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 not expected to disrupt GJB1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245767.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Comment:
GJB1: PP1:Strong, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting
Number of individuals with the variant: 2
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Pathogenic
(Feb 01, 1999)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, X-LINKED DOMINANT, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031414.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 25, 2017 |
Comment on evidence:
Since CX32 is expressed not only in Schwann cells in the peripheral nervous system but also in oligodendrocytes in the central nervous system, Bahr et … (more)
Since CX32 is expressed not only in Schwann cells in the peripheral nervous system but also in oligodendrocytes in the central nervous system, Bahr et al. (1999) examined a CMTX1 (302800) family for evidence of CNS involvement. The family had an asn205-to-ser mutation involving the fourth transmembrane domain of CX32. The patients showed typical clinical and electrophysiologic abnormalities in the peripheral nervous system, but, in addition, visual, acoustic, and motor pathways of the CNS were affected subclinically. This was indicated by pathologic changes in visual evoked potentials, brainstem auditory evoked potentials, and central motor evoked potentials. They suggested that abnormal electrophysiologic findings in CNS pathway examinations should raise the suspicion of CMTX and a search for mutations in the GJB1 gene. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Charcot-Marie-Tooth disease X-linked dominant 1
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000040509.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes. | Adam MP | - | 2024 | PMID: 20301548 |
Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease. | Lu YY | Chinese medical journal | 2017 | PMID: 28469099 |
Phenotypes and cellular effects of GJB1 mutations causing CMT1X in a cohort of 226 Chinese CMT families. | Liu L | Clinical genetics | 2017 | PMID: 27804109 |
Three novel mutations and genetic epidemiology analysis of the Gap Junction Beta 1 (GJB1) gene among Hungarian Charcot-Marie-Tooth disease patients. | Milley GM | Neuromuscular disorders : NMD | 2016 | PMID: 27544631 |
[Clinical and genetic analysis of a Chinese family affected with X-linked Charcot-Marie-Tooth disease]. | Feng Y | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2013 | PMID: 24327141 |
Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations. | Miltenberger-Miltenyi G | European journal of human genetics : EJHG | 2009 | PMID: 19259128 |
Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. | Wang HL | Neurobiology of disease | 2004 | PMID: 15006706 |
Novel mutations in the Charcot-Marie-Tooth disease genes PMP22, MPZ, and GJB1. | Huehne K | Human mutation | 2003 | PMID: 12497641 |
Cellular mechanisms of connexin32 mutations associated with CNS manifestations. | Kleopa KA | Journal of neuroscience research | 2002 | PMID: 12111842 |
The frequency of 17p11.2 duplication and Connexin 32 mutations in 282 Charcot-Marie-Tooth families in relation to the mode of inheritance and motor nerve conduction velocity. | Dubourg O | Neuromuscular disorders : NMD | 2001 | PMID: 11404117 |
Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene. | Bähr M | Journal of neurology, neurosurgery, and psychiatry | 1999 | PMID: 10071100 |
Mutation analysis in Charcot-Marie-Tooth disease type 1 (CMT1). | Sorour E | Human mutation | 1998 | PMID: 9452099 |
Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families. | Rouger H | Human mutation | 1997 | PMID: 9401007 |
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Text-mined citations for rs104894822 ...
HelpRecord last updated Oct 08, 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.