NM_004004.6(GJB2):c.313_326del (p.Lys105fs) AND not provided

Germline classification:: Pathogenic (10 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:: RCV000080370.60

Allele description [Variation Report for NM_004004.6(GJB2):c.313_326del (p.Lys105fs)]

NM_004004.6(GJB2):c.313_326del (p.Lys105fs)

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.313_326del (p.Lys105fs)

HGVS:

NC_000013.11:g.20189258_20189271del
NG_008358.1:g.8707_8720del
NM_004004.6:c.313_326delMANE SELECT
NP_003995.2:p.Lys105fs
LRG_1350t1:c.313_326del
LRG_1350:g.8707_8720del
LRG_1350p1:p.Lys105fs
NC_000013.10:g.20763397_20763410del
NC_000013.10:g.20763397_20763410delCTTGATGAACTTCC
NM_004004.5:c.313_326delAAGTTCATCAAGGG
NM_004004.6:c.313_326delAAGTTCATCAAGGGMANE SELECT
c.313_326del
c.313_326delAAGTTCATCAAGGG (p.Lys105Glyfs*5)
p.Lys105Glyfs*5
p.Lys105fs

Protein change:

K105fs

Links:

OMIM: 121011.0034; dbSNP: rs111033253

NCBI 1000 Genomes Browser:

rs111033253

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
SCV000329860	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 19, 2021)	germline	clinical testing	Citation Link,
SCV000603830	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Feb 3, 2022)	germline	clinical testing	Citation Link,
SCV000613512	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (Oct 20, 2020)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 26896187, 15253766, 12112666, 15967879, 15146474, 27224056, 10218527, 26467025
SCV000700403	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Feb 11, 2015)	germline	clinical testing	Citation Link,
SCV001227363	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10218527, 22567152, 26896187, 27224056, 10874298, 10982180, 15855033, 25708704, 28492532
SCV001245650	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Sep 1, 2023)	germline	clinical testing	Citation Link,
SCV001449875	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 13, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002024256	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 26, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002818209	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]
SCV004225744	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 31, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12112666, 15967879, 26896187, 27224056, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	8	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	11	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

Citations

PubMed

Spectrum and frequencies of mutations in the GJB2 (Cx26) gene among 156 Czech patients with pre-lingual deafness.

Seeman P, Malíková M, Rasková D, Bendová O, Groh D, Kubálková M, Sakmaryová I, Seemanová E, Kabelka Z.

Clin Genet. 2004 Aug;66(2):152-7.

PubMed [citation]

PMID:: 15253766

GJB2 mutations in patients with non-syndromic hearing loss from Northeastern Hungary.

Tóth T, Kupka S, Haack B, Riemann K, Braun S, Fazakas F, Zenner HP, Muszbek L, Blin N, Pfister M, Sziklai I.

Hum Mutat. 2004 Jun;23(6):631-2.

PubMed [citation]

PMID:: 15146474

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000329860.8

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

Description

Frameshift variant predicted to result in protein truncation, as the last 122 amino acids are lost and replaced with 4 incorrect amino acids (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 22975760, 30094485, 10218527, 27224056, 25999548, 22567152, 29701678, 30168495, 30344259, 9529365, 29625052, 31980526, 31160754, 33096615, 31589614, 32067424, 26896187)

#	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, SCV000603830.5

#	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.313_326del; p.Lys105GlyfsTer5 variant (rs111033253) is reported in the literature in individuals affected with hearing loss, both in the homozygous state and in trans to other pathogenic variants (Dalamon 2013, Denoyelle 1999, Kupa 2002, Mikstiene 2016). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 44737) and it is found in the general population with an overall allele frequency of 0.01% (38/281690 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 14 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the c.313_326del variant is considered to be pathogenic. References: Dalamon V et al. Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases. Mol Biol Rep. 2013 Dec;40(12):6945-55. PMID: 24158611. Denoyelle F et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet. 1999 Apr 17;353(9161):1298-303. PMID: 10218527. Kupka S et al. Frequencies of GJB2 mutations in German control individuals and patients showing sporadic non-syndromic hearing impairment. Hum Mutat. 2002 Jul;20(1):77-8. PMID: 12112666. Mikstiene V et al. The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population. BMC Genet. 2016 Feb 19;17:45. PMID: 26896187.

#	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, SCV000613512.2

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

Description

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. 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), SCV000700403.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	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		10	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001227363.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change creates a premature translational stop signal (p.Lys105Glyfs*5) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033253, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with autosomal recessive deafness (PMID: 10218527, 22567152, 26896187, 27224056). ClinVar contains an entry for this variant (Variation ID: 44737). This variant disrupts the p.Pro173, p.Arg184 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10874298, 10982180, 15855033, 25708704). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, SCV001245650.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	not provided

Description

GJB2: PM3:Very Strong, PVS1, 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		7	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449875.1

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

From Revvity Omics, Revvity, SCV002024256.3

#	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, SCV002818209.1

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV004225744.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

PM2_supporting, PM3_very_strong, 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		1	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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