NM_004004.6(GJB2):c.229T>C (p.Trp77Arg) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jan 27, 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:: RCV000080368.33

Allele description [Variation Report for NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)]

NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)

HGVS:

NC_000013.11:g.20189353A>G
NG_008358.1:g.8623T>C
NM_004004.6:c.229T>CMANE SELECT
NP_003995.2:p.Trp77Arg
NP_003995.2:p.Trp77Arg
LRG_1350t1:c.229T>C
LRG_1350:g.8623T>C
LRG_1350p1:p.Trp77Arg
NC_000013.10:g.20763492A>G
P29033:p.Trp77Arg
c.229T>C
c.229T>C (p.Trp77Arg)

Protein change:

W77R; TRP77ARG

Links:

UniProtKB: P29033#VAR_002141; OMIM: 121011.0004; dbSNP: rs104894397

NCBI 1000 Genomes Browser:

rs104894397

Molecular consequence:

NM_004004.6:c.229T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

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
SCV000227324	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Mar 21, 2016)	germline	clinical testing	Citation Link,
SCV000322428	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 29, 2022)	germline	clinical testing	Citation Link,
SCV000958603	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16467727, 16545002, 19371219, 10556284, 12064630, 12505163, 28492532
SCV001959295	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001973315	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002024250	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 8, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Auditory responses in cochlear implant users with and without GJB2 deafness.

Propst EJ, Papsin BC, Stockley TL, Harrison RV, Gordon KA.

Laryngoscope. 2006 Feb;116(2):317-27.

PubMed [citation]

PMID:: 16467727

High incidence of deafness from three frequent connexin 26 mutations in an isolated community.

Zlotogora J, Carasquillo M, Barges S, Shalev SA, Hujerat Y, Chakravarti A.

Genet Test. 2006 Spring;10(1):40-3.

PubMed [citation]

PMID:: 16545002

See all PubMed Citations (8)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000227324.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	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		2	not provided	not provided	not provided

From GeneDx, SCV000322428.10

#	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 that the W77R variant did not form homotypic junctional channels, had impaired intercellular coupling, was inefficiently targeted to the plasma membrane, and was retained in intracellular stores (Martin et al., 1999; Bruzzone et al., 2003); 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: 12064630, 22975760, 14985372, 12505163, 10556284, 9328482, 25388846, 30139988, 15967879, 15964725, 10982180, 11102979, 16380907, 11935342, 22785241, 21726435, 31163360, 31827275, 32747562, 33096615, 31589614, 33105617)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000958603.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 77 of the GJB2 protein (p.Trp77Arg). This variant is present in population databases (rs104894397, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 16467727, 16545002, 19371219). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17003). 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 GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 10556284, 12064630, 12505163). For these reasons, this variant has been classified as Pathogenic.

#	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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001959295.1

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

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001973315.1

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

#	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 Revvity Omics, Revvity, SCV002024250.3

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

#	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: Nov 3, 2024

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