VCV001075826.7 - ClinVar

NM_000166.6(GJB1):c.461_464dup (p.Leu156fs)

Germline

Classification

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.

(1)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000166.6(GJB1):c.461_464dup (p.Leu156fs)

Variation ID: 1075826 Accession: VCV001075826.7

Type and length

Duplication, 4 bp

Location

Cytogenetic: Xq13.1 X: 71224166-71224167 (GRCh38) [ NCBI UCSC ] X: 70444016-70444017 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	May 10, 2021	Feb 28, 2024	Jul 25, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_000166.6:c.461_464dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000157.1:p.Leu156fs	frameshift
NM_001097642.3:c.461_464dup	NP_001091111.1:p.Leu156fs	frameshift
NC_000023.11:g.71224168_71224171dup
NC_000023.10:g.70444018_70444021dup
NG_008357.1:g.13957_13960dup
LRG_245:g.13957_13960dup
LRG_245t2:c.461_464dup	LRG_245p2:p.Leu156fs

... more HGVS ... less HGVS

Protein change

L156fs

Other names

Canonical SPDI

NC_000023.11:71224166:TATCT:TATCTATCT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs2147946234 VarSome

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
Gene	OMIM	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.
GJB1		-	-	GRCh38 GRCh37	795	927

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.
Charcot-Marie-Tooth Neuropathy X	Pathogenic (1)	criteria provided, single submitter	Jul 25, 2020	RCV001389524.7

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.
Pathogenic (Jul 25, 2020)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth Neuropathy X Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001590916.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 7477983‚ 8162049‚ 9364054‚ 21291455 Comment: This sequence change results in a premature translational stop signal in the GJB1 gene (p.Leu156Serfs88). While this is not anticipated to result in nonsense mediated … (more) This sequence change results in a premature translational stop signal in the GJB1 gene (p.Leu156Serfs88). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 128 amino acids of the GJB1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GJB1-related conditions. This variant disrupts the C-terminus of the GJB1 protein. Other variant(s) that disrupt this region (p.Arg220*) have been determined to be pathogenic (PMID: 7477983, 8162049, 9364054, 21291455). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change results in a premature translational stop signal in the GJB1 gene (p.Leu156Serfs*88). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 128 amino acids of the GJB1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GJB1-related conditions. This variant disrupts the C-terminus of the GJB1 protein. Other variant(s) that disrupt this region (p.Arg220*) have been determined to be pathogenic (PMID: 7477983, 8162049, 9364054, 21291455). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
X-linked dominant Charcot-Marie-Tooth disease with connexin 32 (Cx32) mutations in Koreans.	Kim Y	Clinical genetics	2012	PMID: 21291455
Altered trafficking of mutant connexin32.	Deschênes SM	The Journal of neuroscience : the official journal of the Society for Neuroscience	1997	PMID: 9364054
New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease.	Bone LJ	Neurology	1995	PMID: 7477983
Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).	Fairweather N	Human molecular genetics	1994	PMID: 8162049

Text-mined citations for rs2147946234 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000166.6(GJB1):c.461_464dup (p.Leu156fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2147946234 ...