NM_004004.6(GJB2):c.250G>C (p.Val84Leu) AND Nonsyndromic genetic hearing loss

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 21, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001257042.4

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

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

HGVS:

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

Protein change:

V84L; VAL84LEU

Links:

UniProtKB: P29033#VAR_002143; OMIM: 121011.0032; dbSNP: rs104894409

NCBI 1000 Genomes Browser:

rs104894409

Molecular consequence:

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

Observations:

Condition(s)

Name:: Nonsyndromic genetic hearing loss
Synonyms:: Nonsyndromic hearing loss and deafness; Non-syndromic genetic deafness; Nonsyndromic genetic deafness
Identifiers:: MONDO: MONDO:0019497; MedGen: C5680182; Orphanet: 87884

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001433547	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic (Aug 21, 2020)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 24158611, 95239365, 11556849, 12172394, 12189487, 12497637, 14985372, 15365987, 17041943, 12505163, 16217030, 12562518, 30311386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001433547

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Aug 21, 2020)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
Caucasian	germline	yes	1	not provided	not provided	not provided	no	clinical testing

Citations

PubMed

Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases.

Dalamón V, Florencia Wernert M, Lotersztein V, Craig PO, Diamante RR, Barteik ME, Curet C, Paoli B, Mansilla E, Elgoyhen AB.

Mol Biol Rep. 2013 Dec;40(12):6945-55. doi: 10.1007/s11033-013-2814-x. Epub 2013 Oct 25.

PubMed [citation]

PMID:: 24158611

cannot get document summary

See all PubMed Citations (13)

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001433547.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	no	clinical testing	PubMed (13)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.250G>C, p.Val84Leu has a filtering allele frequency of 0.00395% in Latino population from Genome Aggregation Database v2.1.1 (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) meeting PM2 criteria. Computational analysis predicted a pathogenic effect of the variant to the protein (REVELscore=0.947) applying to PP3 rule. This variant was identified in trans with at least 5 known pathogenic variants meeting PM3_VeryStrong criteria (PMID: 24158611, 95239365, 11556849,12172394, 12189487,12497637, 14985372, 15365987, 17041943). The p.Val84Leu change in trans with a pathogenic variant segregated in two affected siblings in a family case. (PP1_Supporting; PMID: 95239365). Dye transfer and electrical coupling assays demonstrated that the variant do not impact the protein function (PMID: 12505163, 12562518, 16217030). However, some assays showed a reduce permeability to IP3 and intracellular exchange of large molecules (PMID: 12505163, 16217030), and therefore this evidence was not counted. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss (PM2, PP3, PM3_VeryStrong and PP1_Supporting).

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

Last Updated: Apr 20, 2025

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