NM_004004.6(GJB2):c.250G>T (p.Val84Leu) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 17, 2023
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:: RCV000790715.27

Allele description [Variation Report for NM_004004.6(GJB2):c.250G>T (p.Val84Leu)]

NM_004004.6(GJB2):c.250G>T (p.Val84Leu)

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.250G>T (p.Val84Leu)

HGVS:

NC_000013.11:g.20189332C>A
NG_008358.1:g.8644G>T
NM_004004.6:c.250G>TMANE SELECT
NP_003995.2:p.Val84Leu
NP_003995.2:p.Val84Leu
LRG_1350t1:c.250G>T
LRG_1350:g.8644G>T
LRG_1350p1:p.Val84Leu
NC_000013.10:g.20763471C>A
NM_004004.5:c.250G>T
P29033:p.Val84Leu

Protein change:

V84L

Links:

UniProtKB: P29033#VAR_002143; dbSNP: rs104894409

NCBI 1000 Genomes Browser:

rs104894409

Molecular consequence:

NM_004004.6:c.250G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000227309	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Feb 24, 2014)	germline	clinical testing	Citation Link,
SCV000958454	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 17, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 11556849, 12172394, 16380907, 19235794, 24013081, 26346709, 12505163, 12562518, 15592461, 16217030, 20441744, 28492532
SCV001751045	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 7, 2022)	germline	clinical testing	Citation Link,
SCV002024248	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 4, 2020)	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	7	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Connexin 26 studies in patients with sensorineural hearing loss.

Kenna MA, Wu BL, Cotanche DA, Korf BR, Rehm HL.

Arch Otolaryngol Head Neck Surg. 2001 Sep;127(9):1037-42.

PubMed [citation]

PMID:: 11556849

Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing.

Wu BL, Lindeman N, Lip V, Adams A, Amato RS, Cox G, Irons M, Kenna M, Korf B, Raisen J, Platt O.

Genet Med. 2002 Jul-Aug;4(4):279-88.

PubMed [citation]

PMID:: 12172394

See all PubMed Citations (13)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000227309.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	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		7	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000958454.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Leu). This variant is present in population databases (rs104894409, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 11556849, 12172394, 16380907, 19235794, 24013081, 26346709). ClinVar contains an entry for this variant (Variation ID: 167134). 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: 12505163, 12562518, 15592461, 16217030, 20441744). 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 GeneDx, SCV001751045.4

#	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 the variant interferes with the metabolic coupling function of the GJB2 protein (Beltramello et al., 2005); This variant is associated with the following publications: (PMID: 12189487, 14985372, 20441744, 12505163, 12562518, 11556849, 9529365, 15592461, 26346709, 16380907, 17426645, 17666888, 31160754)

#	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, SCV002024248.3

#	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: Dec 28, 2024

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