VCV000010431.14 - ClinVar

NM_000166.6(GJB1):c.424C>T (p.Arg142Trp)

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.

(5)

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000166.6(GJB1):c.424C>T (p.Arg142Trp)

Variation ID: 10431 Accession: VCV000010431.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 71224131 (GRCh38) [ NCBI UCSC ] X: 70443981 (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	Apr 4, 2013	Oct 13, 2024	Sep 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000166.6:c.424C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000157.1:p.Arg142Trp	missense
NM_001097642.2:c.424C>T
NM_001097642.3:c.424C>T	NP_001091111.1:p.Arg142Trp	missense
NC_000023.11:g.71224131C>T
NC_000023.10:g.70443981C>T
NG_008357.1:g.13920C>T
LRG_245:g.13920C>T
LRG_245t1:c.424C>T
LRG_245t2:c.424C>T	LRG_245p2:p.Arg142Trp
	P08034:p.Arg142Trp

... more HGVS ... less HGVS

Protein change

R142W

Other names

Canonical SPDI

NC_000023.11:71224130:C:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA255229 UniProtKB: P08034#VAR_002086 OMIM: 304040.0001 dbSNP: rs104894810 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 disease X-linked dominant 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 22, 2024	RCV000011176.7
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 11, 2023	RCV000236641.2
Charcot-Marie-Tooth Neuropathy X	Pathogenic (1)	criteria provided, single submitter	Jan 8, 2024	RCV000474456.10

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 (Jan 11, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000293017.11 First in ClinVar: Jul 25, 2016 Last updated: Jun 17, 2023	Comment: Published functional studies demonstrate a damaging effect, with the R142W variant forming no functional intercellular channels and demonstrating impaired connexon assembly (Bruzzone et al., 1994; … (more) Published functional studies demonstrate a damaging effect, with the R142W variant forming no functional intercellular channels and demonstrating impaired connexon assembly (Bruzzone et al., 1994; VanSlyke et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8004109, 22771394, 10207904, 10848620, 9364054, 8266101, 7946361, 28286897) (less)
Pathogenic (Aug 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked Charcot-Marie-Tooth disease type 1 Affected status: yes Allele origin: maternal	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000999824.1 First in ClinVar: Dec 17, 2019 Last updated: Dec 17, 2019	Publications: PubMed (1) PubMed: 25741868 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30 Number of individuals with the variant: 2 Age: 20-29 years Sex: male
Pathogenic (Jan 08, 2024)	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: SCV000544783.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 8004109‚ 8266101‚ 10873293‚ 25947624‚ 7946361‚ 9364054‚ 10848620‚ 11571214 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 142 of the GJB1 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 142 of the GJB1 protein (p.Arg142Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease, type IX (PMID: 8004109, 8266101, 10873293, 25947624). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10431). 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 expected to disrupt GJB1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 7946361, 9364054, 10848620). This variant disrupts the p.Arg142 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11571214). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease X-linked dominant 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005374319.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024
Pathogenic (Dec 24, 1993)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, X-LINKED DOMINANT, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031403.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 8266101 Comment on evidence: In a family with X-linked Charcot-Marie-Tooth disease (302800), Bergoffen et al. (1993) found a C-to-T transition in codon 142 of the CX32 gene, resulting in … (more) In a family with X-linked Charcot-Marie-Tooth disease (302800), Bergoffen et al. (1993) found a C-to-T transition in codon 142 of the CX32 gene, resulting in substitution of tryptophan for arginine. (less)

Comment:

Published functional studies demonstrate a damaging effect, with the R142W variant forming no functional intercellular channels and demonstrating impaired connexon assembly (Bruzzone et al., 1994; VanSlyke et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8004109, 22771394, 10207904, 10848620, 9364054, 8266101, 7946361, 28286897)

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 142 of the GJB1 protein (p.Arg142Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease, type IX (PMID: 8004109, 8266101, 10873293, 25947624). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10431). 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 expected to disrupt GJB1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 7946361, 9364054, 10848620). This variant disrupts the p.Arg142 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11571214). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
CMTX1 patients' cells present genomic instability corrected by CamKII inhibitors.	Mones S	Orphanet journal of rare diseases	2015	PMID: 25947624
Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease.	Dubourg O	Brain : a journal of neurology	2001	PMID: 11571214
Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins.	VanSlyke JK	Molecular biology of the cell	2000	PMID: 10848620
X-linked Charcot-Marie-Tooth disease and connexin32.	Ionasescu VV	Cell biology international	1998	PMID: 10873293
Altered trafficking of mutant connexin32.	Deschênes SM	The Journal of neuroscience : the official journal of the Society for Neuroscience	1997	PMID: 9364054
Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy.	Ionasescu V	Human molecular genetics	1994	PMID: 8004109
Null mutations of connexin32 in patients with X-linked Charcot-Marie-Tooth disease.	Bruzzone R	Neuron	1994	PMID: 7946361
Connexin mutations in X-linked Charcot-Marie-Tooth disease.	Bergoffen J	Science (New York, N.Y.)	1993	PMID: 8266101

Text-mined citations for rs104894810 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000166.6(GJB1):c.424C>T (p.Arg142Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894810 ...