NM_004004.6(GJB2):c.249C>G (p.Phe83Leu) AND Nonsyndromic genetic hearing loss

Germline classification:: Likely benign (1 submission)
Last evaluated:: Aug 31, 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:: RCV001257146.1

Allele description [Variation Report for NM_004004.6(GJB2):c.249C>G (p.Phe83Leu)]

NM_004004.6(GJB2):c.249C>G (p.Phe83Leu)

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.249C>G (p.Phe83Leu)

HGVS:

NC_000013.11:g.20189333G>C
NG_008358.1:g.8643C>G
NM_004004.6:c.249C>GMANE SELECT
NP_003995.2:p.Phe83Leu
LRG_1350t1:c.249C>G
LRG_1350:g.8643C>G
LRG_1350p1:p.Phe83Leu
NC_000013.10:g.20763472G>C
NM_004004.5:c.249C>G
P29033:p.Phe83Leu
c.249C>G

Protein change:

F83L

Links:

UniProtKB: P29033#VAR_002142; dbSNP: rs111033218

NCBI 1000 Genomes Browser:

rs111033218

Molecular consequence:

NM_004004.6:c.249C>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functionally_normal [Sequence Ontology: SO:0002219]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001433662	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Likely benign (Aug 31, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12505163, 30311386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001433662

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Likely benign
(Aug 31, 2020)

germline

clinical testing

PubMed (2)
[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	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness.

Bruzzone R, Veronesi V, Gomès D, Bicego M, Duval N, Marlin S, Petit C, D'Andrea P, White TW.

FEBS Lett. 2003 Jan 2;533(1-3):79-88.

PubMed [citation]

PMID:: 12505163

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.

Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, Shen J, Chapin A, Boczek NJ, Schimmenti LA, Murry JB, Hasadsri L, Nara K, Kenna M, Booth KT, Azaiez H, Griffith A, Avraham KB, Kremer H, Rehm HL, Amr SS, Abou Tayoun AN; et al.

Hum Mutat. 2018 Nov;39(11):1593-1613. doi: 10.1002/humu.23630.

PubMed [citation]

PMID:: 30311386
PMCID:: PMC6188673

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001433662.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	2	not provided	not provided	clinical testing	PubMed (2)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.249C>G variant (p.Phe83Leu) in GJB2 gene is 0,28% (404/ 29116 European non-Finnish chromosomes with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering supporting evidence against pathogenicity for autosomal recessive hearing loss variants (BS1_Supporting). The p.Phe83Leu change has been identified in trans with a pathogenic dominant variant in a family case with KID syndrome applying to BP2 rule (PMID: 10633135). Functional studies demonstrated that p.Phe83Leu mutant generated electrical conductance like the wild type in Xenopus laevis oocytes. Besides, 100% of dye transfer was detected in HeLa cells expressing p.Phe83Leu mutant (PMID:12505163). Hence, this evidence meets BS3_Sup standard. Therefore, this variant meets criteria to be classified as likely benign for autosomal recessive non-syndromic hearing loss: (BS1_Supporting, BP2 and BS3_Supporting).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	blood	not provided		2	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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