NM_004004.6(GJB2):c.246C>G (p.Ile82Met) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Mar 25, 2019
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:: RCV000169070.5

Allele description [Variation Report for NM_004004.6(GJB2):c.246C>G (p.Ile82Met)]

NM_004004.6(GJB2):c.246C>G (p.Ile82Met)

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.246C>G (p.Ile82Met)

HGVS:

NC_000013.11:g.20189336G>C
NG_008358.1:g.8640C>G
NM_004004.6:c.246C>GMANE SELECT
NP_003995.2:p.Ile82Met
LRG_1350t1:c.246C>G
LRG_1350:g.8640C>G
LRG_1350p1:p.Ile82Met
NC_000013.10:g.20763475G>C
NM_004004.5:c.246C>G

Protein change:

I82M

Links:

dbSNP: rs781534323

NCBI 1000 Genomes Browser:

rs781534323

Molecular consequence:

NM_004004.6:c.246C>G - 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
SCV000220237	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Apr 10, 2014)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 16380907, 15964725, 12112666, 16300957 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001360719	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 25, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16380907, 12112666, 22567152, 20234132, 16300957 Citation Link,
SCV002086060	Natera, Inc.	no assertion criteria provided	Pathogenic (Jan 27, 2021)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000220237

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Apr 10, 2014)

unknown

literature only

PubMed (4)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV001360719

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 25, 2019)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002086060

Natera, Inc.

no assertion criteria provided

Pathogenic
(Jan 27, 2021)

germline

clinical testing

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Prevalence of GJB2 mutations and the del(GJB6-D13S1830) in Argentinean non-syndromic deaf patients.

Dalamón V, Béhèran A, Diamante F, Pallares N, Diamante V, Elgoyhen AB.

Hear Res. 2005 Sep;207(1-2):43-9.

PubMed [citation]

PMID:: 15964725

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 Counsyl, SCV000220237.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	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, SCV001360719.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: GJB2 c.246C>G (p.Ile82Met) results in a conservative amino acid change located in the transmembrane domain (Palmada 2006) 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 8.1e-06 in 246170 control chromosomes (gnomAD). c.246C>G has been reported in the literature in multiple compound heterozygous individuals affected with Non-Syndromic Hearing Loss (Kupka 2002, Bartsch 2010, Danilenko 2012, Snoeckx 2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating profound reduction in channel activity as determined by electrophysiological analysis on Xenopus oocytes expressing the mutant protein (Palmada 2006). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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

From Natera, Inc., SCV002086060.1

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

Last Updated: Jul 23, 2024

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