NM_004004.6(GJB2):c.235del (p.Leu79fs) AND not provided

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jan 31, 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:: RCV000255303.39

Allele description [Variation Report for NM_004004.6(GJB2):c.235del (p.Leu79fs)]

NM_004004.6(GJB2):c.235del (p.Leu79fs)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.235del (p.Leu79fs)

Other names:

NM_004004.5(GJB2):c.235delC(p.Leu79Cysfs); NM_004004.5(GJB2):c.235delC

HGVS:

NC_000013.10:g.20763488delG
NC_000013.11:g.20189349del
NG_008358.1:g.8629del
NM_004004.6:c.235delMANE SELECT
NP_003995.2:p.Leu79fs
LRG_1350t1:c.235del
LRG_1350:g.8629del
LRG_1350p1:p.Leu79fs
NC_000013.10:g.20763486del
NC_000013.10:g.20763486delG
NC_000013.10:g.20763488del
NC_000013.10:g.20763488del
NC_000013.10:g.20763488delG
NC_000013.11:g.20189347delG
NC_000013.11:g.20189349del
NM_004004.5:c.235delC
NM_004004.6:c.235_236delinsTMANE SELECT
NM_004004.6:c.235delCMANE SELECT
c.235delC
c.235delC (p.Leu79Cysfs*3)
p.Leu79Cysfs*3
p.Leu79CysfsX3
p.Leu79fs

Protein change:

L79fs

Links:

OMIM: 121011.0014; dbSNP: rs80338943

NCBI 1000 Genomes Browser:

rs80338943

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
SCV000322427	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 18, 2019)	germline	clinical testing	Citation Link,
SCV000603827	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Mar 13, 2023)	germline	clinical testing	Citation Link,
SCV000613508	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jan 16, 2023)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 10501520, 26119842, 12352684, 20739944, 19043807, 26061264, 26336802, 30589569, 28012523, 30693673, 15479191, 12111646, 10607953, 10633133, 12865758, 15700112, 17505205, 14505035, 12505163, 26467025
SCV000700278	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 21, 2017)	germline	clinical testing	Citation Link,
SCV000938184	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10501520, 15479191, 17505205, 20739944, 22747691, 25266519, 26061264, 27045574, 14505035, 12352684, 20095872, 28492532
SCV002024253	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002818210	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 17, 2022)	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	5	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

GJB2 and mitochondrial 12S rRNA susceptibility mutations in sudden deafness.

Chen K, Sun L, Zong L, Wu X, Zhan Y, Dong C, Cao H, Tang H, Jiang H.

Eur Arch Otorhinolaryngol. 2016 Jun;273(6):1393-8. doi: 10.1007/s00405-015-3693-7. Epub 2015 Jun 29.

PubMed [citation]

PMID:: 26119842

Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population.

Han SH, Park HJ, Kang EJ, Ryu JS, Lee A, Yang YH, Lee KR.

J Hum Genet. 2008;53(11-12):1022-1028. doi: 10.1007/s10038-008-0342-7. Epub 2008 Dec 2.

PubMed [citation]

PMID:: 19043807

See all PubMed Citations (26)

Details of each submission

From GeneDx, SCV000322427.6

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

Description

One of the most common variants reported in the GJB2 gene, with a carrier frequency of 1-2% in the Japanese and Chinese populations (Fuse et al., 1999; Dzhemileva et al., 2010; Yao et al., 2012); Frameshift variant predicted to result in protein truncation, as the last 148 amino acids are lost and replaced with 2 incorrect amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Published functional studies demonstrate a damaging effect; cells expressing c.235delC fail to reach their destination in the cell membrane and have reduced gap junction activity (Choung et al., 2002; Zhang et al., 2010); Classified as pathogenic by the ClinGen Hearing Loss Expert Panel (SCV000840502.3; Oza et al., 2018); This variant is associated with the following publications: (PMID: 12505163, 26336802, 25266519, 26119842, 30275481, 20095872, 25262649, 22975760, 12352684, 23469187, 24945352, 22088281, 15479191, 22747691, 20739944, 17666888, 10501520, 19043807, 26061264, 26763877, 27308839, 27045574, 28012523, 16952406, 12111646, 12169891, 30282152, 29447821, 30589569, 29086887, 29771057, 30693673, 31195736, 30816908, 30036422, 30146550, 31370293, 30733538, 31347505, 31162818, 30344259, 31564438, 29625052, 31914302, 26689913, 31541171, 31827275, 31980526, 31160754, 30896630, 32747562, 22875492, 31589614, 29871260, 32973888, 32708339)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603827.8

#	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.235del; p.Leu79CysfsTer3 variant (rs80338943) is a well-studied variant associated with autosomal recessive nonsyndromic hearing loss (Choung 2002, Du 2016, Fuse 1999, Han 2008, Zhang 2010). This variant is reported in ClinVar (Variation ID: 17014) and is found in the general population with an overall allele frequency of 0.047% (134/282,792 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Choung YH et al. Functional study of GJB2 in hereditary hearing loss. Laryngoscope. 2002 Sep;112(9):1667-71. PMID: 12352684. Du Y et al. Analysis of p.V37I compound heterozygous mutations in the GJB2 gene in Chinese infants and young children. Biosci Trends. 2016 Jul 19;10(3):220-6. PMID: 27350192. Fuse Y et al. Three novel connexin26 gene mutations in autosomal recessive non-syndromic deafness. Neuroreport. 1999 Jun 23;10(9):1853-7. PMID: 10501520. Han SH et al. Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. J Hum Genet. 2008;53(11-12):1022-8. PMID: 19043807. Zhang Y et al. Three common GJB2 mutations causing nonsyndromic hearing loss in Chinese populations are retained in the endoplasmic reticulum. Acta Otolaryngol. 2010 Jul;130(7):799-803. PMID: 20095872.

#	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 Athena Diagnostics, SCV000613508.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

This variant is expected to result in the loss of a functional protein. This variant is one of the most common variants associated with autosomal recessive form of nonsyndromic hearing loss (PMID: 17505205, 19043807, 15700112), therefore the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant impairs gap junction channel activity (PMID: 12352684, 12505163). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

#	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 Eurofins Ntd Llc (ga), SCV000700278.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	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		5	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000938184.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change creates a premature translational stop signal (p.Leu79Cysfs*3) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 148 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338943, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with autosomal recessive non-syndromic hearing loss (PMID: 10501520, 15479191, 17505205, 20739944, 22747691, 25266519, 26061264, 27045574). It is commonly reported in individuals of East Asian ancestry (PMID: 14505035). This variant is also known as c.233delC. ClinVar contains an entry for this variant (Variation ID: 17014). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GJB2 function (PMID: 12352684, 20095872). 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 Revvity Omics, Revvity, SCV002024253.3

#	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

From Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital, SCV002818210.1

#	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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