NM_004004.6(GJB2):c.298C>T (p.His100Tyr) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jun 2, 2023
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:: RCV000169347.14

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]

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 1A (DFNB1A)
Synonyms:: Deafness nonsyndromic, Connexin 26 linked; Deafness, autosomal recessive 1A; DFNB 1 Nonsyndromic Hearing Loss and Deafness; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009076; MedGen: C2673759; Orphanet: 90636; OMIM: 220290

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220715	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Sep 19, 2014)	unknown	literature only	PubMed (11) [See all records that cite these PMIDs] 14694360, 17146393, 10376574, 20553101, 17935238, 17041943, 21912263, 21094084, 14681040, 21287563, 11102979 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000919427	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 11, 2017)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 17935238, 21287563, 21094084, 14681040, 17041943, 14694360, 11216656, 18758381, 16931589, 26749107, 16222667, 11102979, 17666888 Citation Link,
SCV002086052	Natera, Inc.	no assertion criteria provided	Pathogenic (Jul 7, 2020)	germline	clinical testing
SCV003935280	Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 2, 2023)	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Temporal bone imaging in GJB2 deafness.

Propst EJ, Blaser S, Stockley TL, Harrison RV, Gordon KA, Papsin BC.

Laryngoscope. 2006 Dec;116(12):2178-86.

PubMed [citation]

PMID:: 17146393

Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness.

Green GE, Scott DA, McDonald JM, Woodworth GG, Sheffield VC, Smith RJ.

JAMA. 1999 Jun 16;281(23):2211-6.

PubMed [citation]

PMID:: 10376574

See all PubMed Citations (18)

Details of each submission

From Counsyl, SCV000220715.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (11)

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919427.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

Variant summary: The GJB2 c.298C>T (p.His100Tyr) variant causes a missense change involving the alteration of a conserved nucleotide located in the Connexin, N-terminal domain (IPR013092) (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study showed lack of hemichannel permeability/conductivity associated with this variant (Kim_2016). The variant was found in the control population dataset of ExAC in 5/121260 control chromosomes at a frequency of 0.0000412, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant was reported in multiple patients with NSHL (Putcha_2007, Feldmann_2004, Lipan_2011, Burke_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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 Natera, Inc., SCV002086052.1

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

#	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 Integrating Genomics into Medicine, Frazer Institute, University Of Queensland, SCV003935280.1

#	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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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