NM_004004.6(GJB2):c.35del (p.Gly12fs) AND not provided

Germline classification:: Pathogenic (19 submissions)
Last evaluated:: Mar 1, 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:: RCV000080373.69

Allele description [Variation Report for NM_004004.6(GJB2):c.35del (p.Gly12fs)]

NM_004004.6(GJB2):c.35del (p.Gly12fs)

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.35del (p.Gly12fs)

Other names:

NM_004004.5(GJB2):c.35delG(p.Gly12Valfs); NM_004004.5(GJB2):c.35delG

HGVS:

NC_000013.11:g.20189552del
NG_008358.1:g.8429del
NM_004004.6:c.35delMANE SELECT
NP_003995.2:p.Gly12fs
LRG_1350t1:c.35del
LRG_1350:g.8429del
LRG_1350p1:p.Gly12fs
NC_000013.10:g.20763686del
NC_000013.10:g.20763686delC
NC_000013.10:g.20763686delC
NC_000013.10:g.20763691del
NC_000013.10:g.20763691del
NC_000013.10:g.20763691delC
NC_000013.11:g.20189547delC
NM_004004.5:c.35delG
NM_004004.6:c.35delGMANE SELECT
c.35delG
c.35delG (p.Gly12Valfs*2)
p.(Gly12Valfs*2)
p.Gly12Valfs*2
p.Gly12ValfsX2
p.Gly12fs

Protein change:

G12fs

Links:

OMIM: 121011.0005; dbSNP: rs80338939

NCBI 1000 Genomes Browser:

rs80338939

Observations:

212

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
SCV000227317	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Jan 4, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9285800, 23757202 Citation Link,
SCV000257945	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Pathogenic (Nov 16, 2015)	unknown	clinical testing	DGD_Variant_Analysis_Guidelines.docx, Citation Link,
SCV000280697	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 24, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000321725	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 4, 2021)	germline	clinical testing	Citation Link,
SCV000603812	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 7, 2023)	germline	clinical testing	Citation Link,
SCV000613516	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jan 11, 2023)	unknown	clinical testing	PubMed (28) [See all records that cite these PMIDs] 9285800, 20301449, 12176036, 15070423, 21465647, 9328482, 9336442, 17553572, 29362677, 10204859, 15359540, 21910243, 17428550, 10477435, 29501291, 11483639, 10713883, 16336662, 22855627, 24346070, 20739944, 15113126, 22567152, 23489192, 21468573, 10376574, 34440441, 26467025
SCV000950817	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9285800, 9328482, 10751669, 12172392, 12239718, 19925344, 12176036, 28492532
SCV001245655	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2024)	germline	clinical testing	Citation Link,
SCV001448121	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001449612	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 3, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001468968	Laboratoire de Génétique Moléculaire, CHU Bordeaux	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001741167	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001972432	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002009981	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002024267	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 19, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002818274	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]
SCV004024406	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004031351	Molecular Genetics laboratory, Necker Hospital	no assertion criteria provided	Pathogenic (Feb 15, 2019)	biparental	clinical testing
SCV004225747	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 16, 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	not provided	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	clinical testing
not provided	biparental	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	125	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	87	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Free the data: one laboratory's approach to knowledge-based genomic variant classification and preparation for EMR integration of genomic data.

Bean LJ, Tinker SW, da Silva C, Hegde MR.

Hum Mutat. 2013 Sep;34(9):1183-8. doi: 10.1002/humu.22364. Epub 2013 Aug 5.

PubMed [citation]

PMID:: 23757202

Smith RJH, Azaiez H, Booth K.

1998 Sep 28 [updated 2023 Jul 20]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301449

See all PubMed Citations (35)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000227317.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	113	not provided	not provided	clinical testing	PubMed (2)

Description

The c.35delG deletion is the most common pathogenic variant associated with hearing loss. Www.ncbi.nlm.nih.gov/books/NBK1272/1

#	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		113	not provided	not provided	not provided

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000257945.5

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000280697.1

#	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	not provided	not provided	not provided	not provided		not provided	0.011099	not provided	not provided

From GeneDx, SCV000321725.9

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

Description

Case control studies suggest this variant is associated with hearing loss; allele frequency of the variant is significantly higher in individuals with hearing loss compared to individuals in the general population (Tsukada et al., 2015; Sloan-Heggen et al., 2016); Frameshift variant predicted to result in protein truncation, as the last 214 amino acids are lost (Stenson et al., 2014); In vitro studies demonstrate that the c.35delG variant results in loss of connexin 26 function (D'Andrea et al., 2002); Classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840537.3; Oza et al., 2018); This variant is associated with the following publications: (PMID: 20815033, 22975760, 26896187, 29234782, 9819448, 18985073, 25262649, 12833397, 16088916, 21465647, 15070423, 20073550, 19925344, 20739944, 23489192, 27316387, 17666888, 16222667, 27843504, 12189487, 14738110, 25266519, 9285800, 27153395, 26990548, 19274344, 27177047, 25533962, 29501291, 29293505, 29431110, 29016196, 28281779, 17431919, 12169891, 12172392, 30609409, 30730013, 30094485, 29372807, 29542069, 29086887, 30168495, 30390570, 30431684, 31163360, 29907799, 30055715, 31028937, 31370293, 31162818, 30344259, 31564438, 31130284, 31541171, 32279305, 31827275, 31980526, 31160754, 30275481, 10782932, 32747562, 33443819, 14759569, 33096615, 29871260, 33297549, 12068628, 33466560, 33105617, 32067424, 32853555, 32860223, 11355484, 32842620, 31078570, 10713883, 12176036, 26969326, 25999548)

#	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, SCV000603812.10

#	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.35delG; p.Gly12ValfsTer2 variant (rs80338939) is the most common pathogenic GJB2 variant found among individuals with European ancestry (Estivill 1998, Gasparini 2000). It has been described in the homozygous and compound heterozygous state in individuals affected with autosomal recessive nonsyndromic hearing loss with severity ranging from mild to profound (Estivill 1998, Gasparini 2000, Putcha 2007). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 17004) and is observed in the general population at an overall frequency of 0.6% (1737/280696 alleles, 10 homozygotes) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, and in vitro functional studies demonstrate a loss of connexin 26 function (D’Andrea 2002). Based on available information, this variant is considered pathogenic. References: D’Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 Aug 23;296(3):685-91. PMID: 12176036 Estivill X et al. Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 1998 Feb 7;351(9100):394-8. PMID: 9482292 Gasparini P et al. High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG. Eur J Hum Genet. 2000 Jan;8(1):19-23. PMID: 10713883 Putcha G 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. PMID: 17666888

#	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 Inc, SCV000613516.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (28)

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 the recessive form of nonsyndromic hearing loss, DFNB1 (PMID: 20301449), and so 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 is also referred to as 35delG, and sometimes 30delG, in published literature. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. In vitro studies demonstrate this variant results in loss of connexin 26 function (PMID: 12176036).

#	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 Invitae, SCV000950817.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Gly12Valfs*2) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 215 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338939, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 9285800, 9328482, 12239718). It is commonly reported in individuals of European ancestry (PMID: 10751669, 12172392, 12176036, 12239718, 19925344). ClinVar contains an entry for this variant (Variation ID: 17004). 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: 12176036). 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, SCV001245655.20

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	68	not provided	not provided	clinical testing	not provided

Description

GJB2: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting

#	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		68	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001448121.1

#	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 Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449612.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	19	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		19	not provided	not provided	not provided

From Laboratoire de Génétique Moléculaire, CHU Bordeaux, SCV001468968.1

#	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

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001741167.3

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001972432.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009981.3

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

From Revvity Omics, Revvity, SCV002024267.3

#	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, SCV002818274.1

#	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

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV004024406.2

#	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 Molecular Genetics laboratory, Necker Hospital, SCV004031351.1

#	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	biparental	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004225747.1

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

Description

PM3_very_strong, PS4, PVS1

#	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		12	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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