NM_004004.6(GJB2):c.298C>T (p.His100Tyr) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jan 5, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000798119.46

Allele description [Variation Report for NM_004004.6(GJB2):c.298C>T (p.His100Tyr)]

NM_004004.6(GJB2):c.298C>T (p.His100Tyr)

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.298C>T (p.His100Tyr)

HGVS:

NC_000013.11:g.20189284G>A
NG_008358.1:g.8692C>T
NM_004004.6:c.298C>TMANE SELECT
NP_003995.2:p.His100Tyr
LRG_1350t1:c.298C>T
LRG_1350:g.8692C>T
LRG_1350p1:p.His100Tyr
NC_000013.10:g.20763423G>A
NM_004004.5:c.298C>T

Protein change:

H100Y

Links:

dbSNP: rs143343083

NCBI 1000 Genomes Browser:

rs143343083

Molecular consequence:

NM_004004.6:c.298C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000603836	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Oct 7, 2020)	germline	clinical testing	Citation Link,
SCV000937718	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11102979, 16222667, 16467727, 17041943, 20553101, 21094084, 21287563, 21465647, 26749107, 28492532
SCV001371290	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2023)	germline	clinical testing	Citation Link,
SCV001762221	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001825360	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 14, 2021)	germline	clinical testing	Citation Link,
SCV002024269	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 27, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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	clinical testing
not provided	germline	yes	3	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA).

Prasad S, Cucci RA, Green GE, Smith RJ.

Hum Mutat. 2000 Dec;16(6):502-8.

PubMed [citation]

PMID:: 11102979

Connexin 26 variants and auditory neuropathy/dys-synchrony among children in schools for the deaf.

Cheng X, Li L, Brashears S, Morlet T, Ng SS, Berlin C, Hood L, Keats B.

Am J Med Genet A. 2005 Nov 15;139(1):13-8.

PubMed [citation]

PMID:: 16222667

See all PubMed Citations (11)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603836.2

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

Description

The GJB2 c.298C>T; p.His100Tyr variant (rs143343083) has been reported multiple times in the literature in individuals with hearing loss who were compound heterozygous with another pathogenic GJB2 variant (Dodson 2011, Green 1999, Putcha 2007, Siemering 2006, Snoeckx 2005). Additionally, functional studies suggest the variant protein is unable to function properly as a homotypic gap junction (Kim 2016). This variant has also been reported to the ClinVar database (Variation ID: 158607). It is found in the general population with an overall allele frequency of 0.001% (3/250900 alleles) in the Genome Aggregation Database. The histidine at codon 100 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Dodson KM et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011 May;155A(5):993-1000. Green GE et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Kim HR et al. The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis. Hum Genet. 2016 Mar;135(3):287-98. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Siemering K et al. Detection of mutations in genes associated with hearing loss using a microarray-based approach. J Mol Diagn. 2006 Sep;8(4):483-9. Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000937718.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 100 of the GJB2 protein (p.His100Tyr). This variant is present in population databases (rs143343083, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 11102979, 16222667, 16467727, 17041943, 20553101, 21094084, 21287563, 21465647). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 158607). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 26749107). For these reasons, this variant has been classified as Pathogenic.

#	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

From CeGaT Center for Human Genetics Tuebingen, SCV001371290.22

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

GJB2: PM3:Very Strong, PM2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001762221.1

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

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

From GeneDx, SCV001825360.3

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

Description

Published functional studies demonstrate a damaging effect on hemichannel permeability (Kim et al., 2016); Different missense changes at this residue (p.(H100L), p.(H100P), p.(H100Q)) have been reported as pathogenic in the published literature in association with autosomal recessive nonsyndromic hearing loss (Snoeckx et al., 2005; Bartsch et al., 2010; Kim et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 10376574, 31160754, 25388846, 20553101, 14694360, 17935238, 21287563, 12865758, 11102979, 17666888, 16950989, 17041943, 16380907, 21465647, 31980526, 16931589, 26778469, 16467727, 26749107, 20234132)

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

From Revvity Omics, Revvity, SCV002024269.3

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

#	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: Sep 29, 2024

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