NM_004004.6(GJB2):c.167del (p.Leu56fs) 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:: RCV000255988.53

Allele description [Variation Report for NM_004004.6(GJB2):c.167del (p.Leu56fs)]

NM_004004.6(GJB2):c.167del (p.Leu56fs)

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.167del (p.Leu56fs)

Other names:

NM_004004.5(GJB2):c.167delT(p.Leu56Argfs); NM_004004.5(GJB2):c.167delT

HGVS:

NC_000013.11:g.20189415_20189415delA
NC_000013.11:g.20189415del
NG_008358.1:g.8561del
NM_004004.6:c.167delMANE SELECT
NP_003995.2:p.Leu56fs
LRG_1350t1:c.167del
LRG_1350:g.8561del
LRG_1350p1:p.Leu56fs
NC_000013.10:g.20763554del
NC_000013.10:g.20763554delA
NC_000013.11:g.20189415_20189415delA
NC_000013.11:g.20189415delA
NM_004004.5:c.167delT
NM_004004.6:c.167delTMANE SELECT
c.167delT
c.167delT (p.Leu56Argfs*26)
p.Leu56Argfs*26
p.Leu56ArgfsX26
p.Leu56fs

Protein change:

L56fs

Links:

OMIM: 121011.0010; dbSNP: rs80338942

NCBI 1000 Genomes Browser:

rs80338942

Molecular consequence:

NM_004004.6:c.167del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000321727	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 5, 2019)	germline	clinical testing	Citation Link,
SCV000330926	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Jul 30, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000613506	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (May 24, 2022)	unknown	clinical testing	PubMed (17) [See all records that cite these PMIDs] 15967879, 9819448, 16380907, 20739944, 10982182, 26236732, 26096904, 24529908, 24158611, 22785241, 22695344, 21465647, 17666888, 19125024, 11935342, 9285800, 26467025
SCV000940600	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] 9819448, 10982182, 11935342, 15967879, 16380907, 21465647, 22695344, 24158611, 28492532
SCV001160051	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Dec 9, 2022)	germline	clinical testing	Citation Link,
SCV001334475	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Feb 1, 2020)	germline	clinical testing	Citation Link,
SCV002024265	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 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	3	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

Carrier frequency of GJB2 gene mutations c.35delG, c.235delC and c.167delT among the populations of Eurasia.

Dzhemileva LU, Barashkov NA, Posukh OL, Khusainova RI, Akhmetova VL, Kutuev IA, Gilyazova IR, Tadinova VN, Fedorova SA, Khidiyatova IM, Lobov SL, Khusnutdinova EK.

J Hum Genet. 2010 Nov;55(11):749-54. doi: 10.1038/jhg.2010.101. Epub 2010 Aug 26.

PubMed [citation]

PMID:: 20739944

Cochlear Implant Outcomes and Genetic Mutations in Children with Ear and Brain Anomalies.

Busi M, Rosignoli M, Castiglione A, Minazzi F, Trevisi P, Aimoni C, Calzolari F, Granieri E, Martini A.

Biomed Res Int. 2015;2015:696281. doi: 10.1155/2015/696281. Epub 2015 Jul 5.

PubMed [citation]

PMID:: 26236732
PMCID:: PMC4506828

See all PubMed Citations (19)

Details of each submission

From GeneDx, SCV000321727.7

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

Description

Most individuals heterozygous for the c.167delT variant have normal hearing, although subclinical differences in the otoacoustic emissions of carriers has been noted upon audiologic examination (Morell et al., 1998); Frameshift variant predicted to result in protein truncation, as the last 171 amino acids are lost and replaced with 25 incorrect amino acids (Stenson et al., 2014); Classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840535.3; Oza et al., 2018); Observed in 218/276720 (0.08%) alleles from individuals in large population cohorts, including 3 homozygous individuals (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27153395, 28702509, 22785241, 17666888, 24158611, 31160754, 25262649, 21465647, 22975760, 20739944, 11668644, 9819448, 26896187, 9285800, 26990548, 16380907, 15967879, 10982182, 23891399, 10903123, 20301449, 26096904, 24529908, 19125024, 15547683, 26236732, 11935342, 11386851, 29542069, 29984802, 27018795, 29431110, 11074495, 31370293, 31827275, 31980526, 32747562, 33096615, 31589614, 32067424)

#	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 Eurofins Ntd Llc (ga), SCV000330926.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	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		11	not provided	not provided	not provided

From Athena Diagnostics, SCV000613506.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

This variant is expected to result in the loss of a functional protein. This variant is the most common pathogenic variant among the Ashkenazi Jewish population (PMID: 9819448), and therefore, the observed frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with nonsyndromic hearing loss, this variant has been seen with a single recessive pathogenic variant in the same gene.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000940600.6

#	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.Leu56Argfs*26) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 171 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338942, gnomAD 1.6%), 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 deafness (PMID: 15967879, 16380907, 21465647, 22695344, 24158611). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 9819448, 10982182, 11935342, 15967879, 16380907, 21465647, 22695344, 24158611). ClinVar contains an entry for this variant (Variation ID: 17010). 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160051.4

#	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.167delT; p.Leu56fs variant (rs80338942) creates a frameshift and is predicted to result in a truncated protein or absent transcript. Homozygous and compound heterozygous c.167delT variants have been reported in a number of patients with hearing loss (Kenna 2010, Snoeckx 2005). This variant is reported to ClinVar (Variation ID: 17010), and observed in the general population databases with an overall allele frequency of 0.08 percent (218/276720 alleles), including 3 homozygotes (Genome Aggregation Database). Importantly, this variant has been reported at a carrier frequency of 2.4-7.5 percent in Ashkenazi Jewish individuals (Bors 2004, Lerer 2000, Morell 1998, Sobe 1999). Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for c.167delT: https://www.ncbi.nlm.nih.gov/clinvar/variation/17010/ Bors A. et al. Frequencies of two common mutations (c.35delG and c.167delT) of the connexin 26 gene in different populations of Hungary. Int J Mol Med. 2004; 14(6):1105-1108. Gualandi F et al. Exploring the clinical and epidemiological complexity of GJB2-linked deafness. Am J Med Genet. 2002 Sep 15;112(1):38-45. Kenna MA et al. Audiologic Phenotype and Progression in GJB2 (Connexin 26) Hearing Loss. Arch Otolaryngol Head Neck Surg 2010; 136(1):81-87. Lerer I et al. Contribution of connexin 26 mutations in non-syndromic deafness in Ashkenazi patients and the variable phenotypic effect of the mutation 167delT. Am. J. Med. Genet. 2000; 95:53-56. Morell RJ et al. Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med. 1998; 339(21):1500-1505. Snoeckx RL et al. GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study. Am J Hum Genet 2005; 77:945-957. Sobe T et al. High frequency of the deafness-associated 167delT mutation in the connexin 26 (GJB2) gene in Israeli Ashkenazim. Am J Med Genet. 1999; 86:499-500.

#	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, SCV001334475.25

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

From Revvity Omics, Revvity, SCV002024265.3

#	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: Nov 3, 2024

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