NM_004004.6(GJB2):c.283G>A (p.Val95Met) AND Autosomal recessive nonsyndromic hearing loss 1A

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Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 27, 2022
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:: RCV002228125.2

Allele description

NM_004004.6(GJB2):c.283G>A (p.Val95Met)

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.283G>A (p.Val95Met)

HGVS:

NC_000013.11:g.20189299C>T
NG_008358.1:g.8677G>A
NM_004004.6:c.283G>AMANE SELECT
NP_003995.2:p.Val95Met
LRG_1350t1:c.283G>A
LRG_1350:g.8677G>A
LRG_1350p1:p.Val95Met
NC_000013.10:g.20763438C>T
NM_004004.5:c.283G>A
P29033:p.Val95Met
c.283G>A
p.VAL95MET

Protein change:

V95M

Links:

UniProtKB: P29033#VAR_002144; dbSNP: rs111033299

NCBI 1000 Genomes Browser:

rs111033299

Molecular consequence:

NM_004004.6:c.283G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 1A (DFNB1A)
Synonyms:: Deafness nonsyndromic, Connexin 26 linked; Deafness, autosomal recessive 1A; DFNB 1 Nonsyndromic Hearing Loss and Deafness; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009076; MedGen: C2673759; Orphanet: 90636; OMIM: 220290

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002511670	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 27, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9529365, 14985372, 12865758, 16222667, 24158611, 12081719, 21481246, 16217030, 23503914 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002511670

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 27, 2022)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

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

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

A genotype-phenotype correlation for GJB2 (connexin 26) deafness.

Cryns K, Orzan E, Murgia A, Huygen PL, Moreno F, del Castillo I, Chamberlin GP, Azaiez H, Prasad S, Cucci RA, Leonardi E, Snoeckx RL, Govaerts PJ, Van de Heyning PH, Van de Heyning CM, Smith RJ, Van Camp G.

J Med Genet. 2004 Mar;41(3):147-54.

PubMed [citation]

PMID:: 14985372
PMCID:: PMC1735685

See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511670.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: GJB2 c.283G>A (p.Val95Met) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251540 control chromosomes (gnomAD, Cheng_2005, Kelley_1998). This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.8e-05 vs 0.025), allowing no conclusion about variant significance. c.283G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Castro_2013, Cheng_2005, Cryns_2004, Kelley_1998, Dalamon_2013). These data indicate that the variant is very likely to be associated with disease. One publication reports that the variant negatively impacted large molecule trafficking across gap junctions, thereby disrupting gap junction mediated intracellular signaling (Zhang_2005). Nine ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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

Last Updated: Jun 17, 2024

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