NM_000166.6(GJB1):c.643C>T (p.Arg215Trp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 26, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000236009.4

Allele description [Variation Report for NM_000166.6(GJB1):c.643C>T (p.Arg215Trp)]

NM_000166.6(GJB1):c.643C>T (p.Arg215Trp)

Gene:

GJB1:gap junction protein beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NM_000166.6(GJB1):c.643C>T (p.Arg215Trp)

HGVS:

NC_000023.11:g.71224350C>T
NG_008357.1:g.14139C>T
NM_000166.6:c.643C>TMANE SELECT
NM_001097642.3:c.643C>T
NP_000157.1:p.Arg215Trp
NP_001091111.1:p.Arg215Trp
LRG_245t2:c.643C>T
LRG_245:g.14139C>T
LRG_245p2:p.Arg215Trp
NC_000023.10:g.70444200C>T
NM_000166.5:c.643C>T
P08034:p.Arg215Trp

Protein change:

R215W

Links:

UniProtKB: P08034#VAR_002129; dbSNP: rs879254099

Molecular consequence:

NM_000166.6:c.643C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.643C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000293451	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 26, 2024)	germline	clinical testing	Citation Link,
SCV000613497	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Nov 18, 2016)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 8162049, 8816997, 9187667, 8698335, 11437164, 11835375, 11571214, 16912585, 10732813, 10234007, 25947624, 22464564, 8990008, 21291455, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000293451

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 26, 2024)

germline

clinical testing

Citation Link,

SCV000613497

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Nov 18, 2016)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).

Fairweather N, Bell C, Cochrane S, Chelly J, Wang S, Mostacciuolo ML, Monaco AP, Haites NE.

Hum Mol Genet. 1994 Jan;3(1):29-34. Erratum in: Hum Mol Genet 1994 Jun;3(6):1034.

PubMed [citation]

PMID:: 8162049

Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects.

Omori Y, Mesnil M, Yamasaki H.

Mol Biol Cell. 1996 Jun;7(6):907-16.

PubMed [citation]

PMID:: 8816997
PMCID:: PMC275942

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000293451.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate a damaging effect as R215W prevents the formation of functional channels (PMID: 8816997, 10234007); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 10234007, 11835375, 8162049, 11571214, 32376792, 34326750, 8816997)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV000613497.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 12, 2026

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