NM_004004.6(GJB2):c.516G>C (p.Trp172Cys) AND Nonsyndromic genetic hearing loss

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 28, 2019
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:: RCV001004778.1

Allele description [Variation Report for NM_004004.6(GJB2):c.516G>C (p.Trp172Cys)]

NM_004004.6(GJB2):c.516G>C (p.Trp172Cys)

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.516G>C (p.Trp172Cys)

HGVS:

NC_000013.11:g.20189066C>G
NG_008358.1:g.8910G>C
NM_004004.5(GJB2):c.516G>C
NM_004004.6:c.516G>CMANE SELECT
NP_003995.2:p.Trp172Cys
LRG_1350t1:c.516G>C
LRG_1350:g.8910G>C
LRG_1350p1:p.Trp172Cys
NC_000013.10:g.20763205C>G
NM_004004.5(GJB2):c.516G>C
NM_004004.5:c.516G>C

Protein change:

W172C

Links:

dbSNP: rs1302739538

NCBI 1000 Genomes Browser:

rs1302739538

Molecular consequence:

NM_004004.6:c.516G>C - 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

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
SCV001164260	ClinGen Hearing Loss Variant Curation Expert Panel	reviewed by expert panel (ClinGen HL ACMG Specifications v1)	Pathogenic (Jul 28, 2019)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 20201936, 31195736, 15790391 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001164260

ClinGen Hearing Loss Variant Curation Expert Panel

reviewed by expert panel

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Jul 28, 2019)

germline

curation

PubMed (3)
[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	curation

Citations

PubMed

GJB2 mutations in Mongolia: complex alleles, low frequency, and reduced fitness of the deaf.

Tekin M, Xia XJ, Erdenetungalag R, Cengiz FB, White TW, Radnaabazar J, Dangaasuren B, Tastan H, Nance WE, Pandya A.

Ann Hum Genet. 2010 Mar;74(2):155-64. doi: 10.1111/j.1469-1809.2010.00564.x. Epub 2010 Jan 27.

PubMed [citation]

PMID:: 20201936
PMCID:: PMC4739516

Unique Mutational Spectrum of the GJB2 Gene and its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys).

Posukh OL, Zytsar MV, Bady-Khoo MS, Danilchenko VY, Maslova EA, Barashkov NA, Bondar AA, Morozov IV, Maximov VN, Voevoda MI.

Genes (Basel). 2019 Jun 5;10(6). doi:pii: E429. 10.3390/genes10060429.

PubMed [citation]

PMID:: 31195736
PMCID:: PMC6627114

See all PubMed Citations (3)

Details of each submission

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV001164260.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

The p.Trp172Cys variant in the GJB2 gene was absent from gnomAD (PM2). However, this variant has been identified at an allele frequency of 1.9% (6/314) in unaffected Tuvinian individuals (PMID: 20201936). This frequency would normally lead to application of BA1 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, the variant was found to have a statistically higher prevalence in affected Tuvinian individuals (66/440 alleles) over ethnically-matched controls (6/314 alleles) (15% vs 1.9%; p<0.0001, PS4; PMID: 20201936) suggesting that this is actually a high frequency founder variant in this population. This variant has been detected in trans with two pathogenic variants in probands with hearing loss (PM3_supporting PMID:20201936; 15790391). The p.Trp172Cys variant in GJB2 has been reported to segregate with hearing loss in at least 9 affected family members (PP1_Strong; PMID: 20201936). The REVEL computational prediction analysis tool produced a score of 0.7 (rounded up from 0.687), which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PS4, PP1_Strong, PP3, PM3_supporting).

#	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: Dec 24, 2023

ClinVar

Relating variation to medicine