NM_004004.6(GJB2):c.250G>C (p.Val84Leu) AND Rare genetic deafness

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 22, 2017
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:: RCV000211770.6

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:: Rare genetic deafness
Identifiers:: MedGen: C5680250; Orphanet: 96210

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061492	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jun 22, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9529365, 11556849, 15592461, 16380907, 14985372, 17426645, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061492

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jun 22, 2017)

germline

clinical testing

PubMed (7)
[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	not provided	7	4	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss.

Kelley PM, Harris DJ, Comer BC, Askew JW, Fowler T, Smith SD, Kimberling WJ.

Am J Hum Genet. 1998 Apr;62(4):792-9.

PubMed [citation]

PMID:: 9529365
PMCID:: PMC1377046

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

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061492.5

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

Description

The p.Val84Leu variant in GJB2 has been reported in 7 individuals with hearing l oss, 6 of whom were compound heterozygous for a second pathogenic variant and 1 of whom was homozygous for the variant, and segregated in 3 affected siblings wi th hearing loss (Cryns 2004, Kelley 1998, Kenna 2001, LMM Unpublished data). Thi s variant was identified in 4/33580 Latino chromosomes; however, this frequency is low enough to be consistent with a recessive carrier frequency. Functional st udies indicate that the Val84Leu variant compromises connexin 26 protein functio n (Beltramello 2005). In summary, this variant meets criteria to be classified a s pathogenic for autosomal recessive hearing loss based on the previously report ed individuals, segregation data, and low frequency in the general population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		7	not provided	4	not provided

Last Updated: Apr 20, 2025

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