NM_004004.6(GJB2):c.229T>C (p.Trp77Arg) 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:: RCV001257039.10

Allele description [Variation Report for NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)]

NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)

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.229T>C (p.Trp77Arg)

HGVS:

NC_000013.11:g.20189353A>G
NG_008358.1:g.8623T>C
NM_004004.6:c.229T>CMANE SELECT
NP_003995.2:p.Trp77Arg
NP_003995.2:p.Trp77Arg
LRG_1350t1:c.229T>C
LRG_1350:g.8623T>C
LRG_1350p1:p.Trp77Arg
NC_000013.10:g.20763492A>G
P29033:p.Trp77Arg
c.229T>C
c.229T>C (p.Trp77Arg)

Protein change:

W77R; TRP77ARG

Links:

UniProtKB: P29033#VAR_002141; OMIM: 121011.0004; dbSNP: rs104894397

NCBI 1000 Genomes Browser:

rs104894397

Molecular consequence:

NM_004004.6:c.229T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

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
SCV001433544	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic (Aug 21, 2020)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 9328482, 11935342, 15964725, 16088916, 16380907, 22785241, 16467727, 16545002, 19371219, 10556284, 12064630, 12505163, 30311386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001433544

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Aug 21, 2020)

germline

clinical testing

PubMed (13)
[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	not provided	clinical testing

Citations

PubMed

Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations.

Carrasquillo MM, Zlotogora J, Barges S, Chakravarti A.

Hum Mol Genet. 1997 Nov;6(12):2163-72.

PubMed [citation]

PMID:: 9328482

Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East.

Shahin H, Walsh T, Sobe T, Lynch E, King MC, Avraham KB, Kanaan M.

Hum Genet. 2002 Mar;110(3):284-9. Epub 2002 Feb 8.

PubMed [citation]

PMID:: 11935342

See all PubMed Citations (13)

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001433544.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	no	clinical testing	PubMed (13)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.229T>C, p.Trp77Arg variant has a filtering allele frequency of 0,00949% (7/34590 of Latino alleles with 95% CI) from Genome Aggregation Database v2.1.1 (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_supporting criteria. This variant has been identified in trans with different pathogenic variants in at least four patients: (PMID: 9328482, 11935342, 15964725, 16088916, 16380907, 22785241, PMID:16467727, 16545002, 19371219) applying to PM3_VeryStrong. Computational evidence showed a damage impact of the mutation to the protein (REVEL: 0.934) meeting PP3 rule. Functional studies in HeLa cells and Xenopus laevis oocytes demonstrated a deleterious effect of the mutant without dominant effect to Human CX26 by dye transfer and junctional conductance measurements assays. In both cases the levels of dye transfer and conductance did not exceed background levels (PMID: 10556284, PMID: 12064630, PMID: 12505163) applying to PS3_Moderate rule. Therefore, the c.229T>C variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2_Supporting, 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

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