NM_004004.6(GJB2):c.339T>G (p.Ser113Arg) AND Nonsyndromic genetic hearing loss

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 17, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001004771.5

Allele description [Variation Report for NM_004004.6(GJB2):c.339T>G (p.Ser113Arg)]

NM_004004.6(GJB2):c.339T>G (p.Ser113Arg)

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.339T>G (p.Ser113Arg)

Other names:

NM_004004.6(GJB2):c.339T>G

HGVS:

NC_000013.11:g.20189243A>C
NG_008358.1:g.8733T>G
NM_004004.6:c.339T>GMANE SELECT
NP_003995.2:p.Ser113Arg
LRG_1350t1:c.339T>G
LRG_1350:g.8733T>G
LRG_1350p1:p.Ser113Arg
NC_000013.10:g.20763382A>C
NM_004004.5(GJB2):c.339T>G
NM_004004.5:c.339T>G
P29033:p.Ser113Arg

Protein change:

S113R

Links:

UniProtKB: P29033#VAR_002145; dbSNP: rs80338946

Molecular consequence:

NM_004004.6:c.339T>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001164251	ClinGen Hearing Loss Variant Curation Expert Panel	reviewed by expert panel (Clingen Hl Acmg Specifications Cdh23 Coch Gjb2 Kcnq4 Myo6 Myo7a Slc26a4 Tecta Ush2a V2)	Uncertain Significance (Jan 17, 2024)	germline	curation	Citation Link,
SCV003800953	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 17, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9529365, 16380907, 12505163, 16950989, 12408072, 24078562 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001164251

ClinGen Hearing Loss Variant Curation Expert Panel

reviewed by expert panel

(Clingen Hl Acmg Specifications Cdh23 Coch Gjb2 Kcnq4 Myo6 Myo7a Slc26a4 Tecta Ush2a V2)

Uncertain Significance
(Jan 17, 2024)

germline

curation

Citation Link,

SCV003800953

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 17, 2023)

germline

clinical testing

PubMed (6)
[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, curation

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

GJB2 mutations and degree of hearing loss: a multicenter study.

Snoeckx RL, Huygen PL, Feldmann D, Marlin S, Denoyelle F, Waligora J, Mueller-Malesinska M, Pollak A, Ploski R, Murgia A, Orzan E, Castorina P, Ambrosetti U, Nowakowska-Szyrwinska E, Bal J, Wiszniewski W, Janecke AR, Nekahm-Heis D, Seeman P, Bendova O, Kenna MA, Frangulov A, et al.

Am J Hum Genet. 2005 Dec;77(6):945-57. Epub 2005 Oct 19.

PubMed [citation]

PMID:: 16380907
PMCID:: PMC1285178

See all PubMed Citations (6)

Details of each submission

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV001164251.4

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

Description

The c.339T>G variant in GJB2 is a missense variant predicted to cause substitution of serine by arginine at amino acid 113. The highest population minor allele frequency in gnomAD v4.0.0 is 0.02% (7/26136 alleles) in the Ashkenazi Jewish population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL provides a score of 0.553 which is neither above nor below the thresholds predicting a damaging or benign impact on GJB2 function (PP3 and BP4 are not met). An in vitro functional study performed in Xenopus oocytes showed that variant junctional conductance for p.Ser113Arg was similar to water (negative control), indicating a loss of function impact on protein function (PS3_Moderate; PMID:12505163). The p.Ser113Arg variant has been reported in several probands with hearing loss, including 3 individuals with a second pathogenic variant without phase confirmation (1.5 points, PM3, PMID: 15365987, 11439000, 9529365, 16380907, 24078562). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PS3_Moderate, PM3. (ClinGen Hearing Loss VCEP specifications version 2; 01/17/2024).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003800953.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: GJB2 c.339T>G (p.Ser113Arg) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250234 control chromosomes. c.339T>G has been reported in the literature as a compound heterozygous genotype in at-least two individuals reportedly affected with features of non syndromic hearing loss (NSHL) and as a non-informative genotype (second allele not specified) in many non syndromic hearing loss cohorts (example, Kelley_1998, McGuirt_2002, Gardner_2006, Snoeckx_2005, Wang_2013). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Bruzzone_2003). The most pronounced variant effect results in loss of junctional conductance due to inability to form homotypic junctional channels. Two clinical diagnostic laboratories and an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3 including the expert panel; Likely pathogenic, n=2) citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely 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: Apr 12, 2026

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