NM_004004.6(GJB2):c.56G>C (p.Ser19Thr) AND Nonsyndromic genetic hearing loss

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 3, 2024
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:: RCV001257035.4

Allele description [Variation Report for NM_004004.6(GJB2):c.56G>C (p.Ser19Thr)]

NM_004004.6(GJB2):c.56G>C (p.Ser19Thr)

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.56G>C (p.Ser19Thr)

Other names:

NM_004004.5(GJB2):c.56G>C; NM_004004.6(GJB2):c.56G>C

HGVS:

NC_000013.11:g.20189526C>G
NG_008358.1:g.8450G>C
NM_004004.6:c.56G>CMANE SELECT
NP_003995.2:p.Ser19Thr
LRG_1350t1:c.56G>C
LRG_1350:g.8450G>C
LRG_1350p1:p.Ser19Thr
NC_000013.10:g.20763665C>G
NM_004004.5:c.56G>C

Protein change:

S19T

Links:

dbSNP: rs80338941

NCBI 1000 Genomes Browser:

rs80338941

Molecular consequence:

NM_004004.6:c.56G>C - 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
SCV001433540	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic (Aug 21, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10982180, 15146674, 24158611, 16077952, 12176036, 30311386
SCV002520695	ClinGen Hearing Loss Variant Curation Expert Panel	reviewed by expert panel (Clingen Hl Acmg Specifications Cdh23 Coch Gjb2 Kcnq4 Myo6 Myo7a Slc26a4 Tecta Ush2a V2)	Pathogenic (Jan 3, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001433540

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Aug 21, 2020)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002520695

ClinGen Hearing Loss Variant Curation Expert Panel

reviewed by expert panel

(Clingen Hl Acmg Specifications Cdh23 Coch Gjb2 Kcnq4 Myo6 Myo7a Slc26a4 Tecta Ush2a V2)

Pathogenic
(Jan 3, 2024)

germline

curation

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
Caucasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene.

Rabionet R, Zelante L, López-Bigas N, D'Agruma L, Melchionda S, Restagno G, Arbonés ML, Gasparini P, Estivill X.

Hum Genet. 2000 Jan;106(1):40-4.

PubMed [citation]

PMID:: 10982180

[Hunting and the brain! Difficult decisions in connection with firearms permits].

Frank K, Böhm MM.

Lakartidningen. 2004 Apr 7;101(15-16):1430-1. Swedish. No abstract available.

PubMed [citation]

PMID:: 15146674

See all PubMed Citations (6)

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001433540.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	no	clinical testing	PubMed (6)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.56G>C, p.Ser19Thr variant has been found only in European non-finish population with a filtering allele frequency of 0,00072% (3/112070 chromosomes with 95% CI) from gnomAD v2.1.1 database meeting PM2 criteria. This variant has been identified in trans with pathogenic variants in at least 4 individuals with hearing impairment (PMID: 10982180, 15146674,24158611,16077952) applying to PM3_VeryStrong criteria. Besides, p.Ser19Thr change in trans with p.Met34Thr variant segregated in two affected siblings (PMID:16077952), so PP1_Moderate rule applied. Functional analysis in HeLa cells demonstrated a deleterious effect of the variant since no dye transfer was observed in mutant (PMID: 12176036) applying to PS3_Moderate rule. Therefore, the c.56G>C variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PM3_VeryStrong, PP1_Moderate 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

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV002520695.3

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

Description

The variant NM_004004.6:c.56G>C in GJB2 is a missense variant predicted to cause substitution of serine by threonine at amino acid 19 (p.Ser19Thr). The highest filtering allele frequency in gnomAD v4 is 0.00111% (19/1111946 CI 95%) in the non-Finnish European population (PM2_Supporting). This variant has been detected in 5 probands with hearing loss. For 4 of those probands, a pathogenic or suspected-pathogenic variants was observed in trans (PM3_VeryStrong; PMIDs: 16077952, 26553399, 10982180, 15146474, Partners Laboratory for Molecular Medicine internal data). Of note, 1 proband was compound-heterozygous for Ser19Thr with c.35delG and also carried Arg32Ser in cis; another proband had Ser19Thr, Arg32Ser and E47* in unspecified zygosity though it is assumed that Ser19Thr and Arg32Ser were in cis based on prior observation. These cases were not counted towards PM3 because contribution of the Arg32Ser variant can not be ruled out. The p.Ser19Thr variant has been reported to segregate with hearing loss in one affected family member (PP1, PMID: 16077952). A functional study has shown that p.Ser19Thr impacts protein function (PS3_Moderate; PMID: 12176036). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nonsyndromic sensorineural hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP1 (ClinGen Hearing Loss VCEP specifications version 2; 1/3/24).

#	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: Oct 26, 2024

ClinVar

Relating variation to medicine