NM_004004.6(GJB2):c.246C>G (p.Ile82Met) 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:: RCV001257041.1

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]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001433546	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic (Aug 21, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15964725, 16380907, 12112666, 16300957, 30311386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001433546

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Aug 21, 2020)

germline

clinical testing

PubMed (5)
[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

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 (5)

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001433546.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	no	clinical testing	PubMed (5)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.246C>G, p.Ile82Met is only present in european non-finish population with a filtering variant frequency of 0,00031% 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. This variant was identified in trans with several pathogenic variants at least four times applying to PM3_VeryStrong (PMID:15964725,16380907,12112666). Besides, p.Ile82Met change in trans with c.35delG variant segregated in two affected meeting PP1_Moderate criteria (PMID: 12112666). Computational evidence showed a damage impact of the mutation to the protein (REVEL: 0.928) meeting PP3 rule. Functional studies in Xenopus Laevis oocytes demonstrated a deleterious effect since there was a significantly decrease of current measure when p.Ile82Met was injected compared to wild type channels (PMID: 16300957) applying to PS3_Moderate. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss (PM2, PP1_Moderate, PM3_VeryStrong, PP3 and PS3_Moderate).

#	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: Nov 3, 2024

ClinVar

Relating variation to medicine