NM_004004.6(GJB2):c.169C>T (p.Gln57Ter) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 26, 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:: RCV000711347.20

Allele description [Variation Report for NM_004004.6(GJB2):c.169C>T (p.Gln57Ter)]

NM_004004.6(GJB2):c.169C>T (p.Gln57Ter)

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.169C>T (p.Gln57Ter)

HGVS:

NC_000013.11:g.20189413G>A
NG_008358.1:g.8563C>T
NM_004004.6:c.169C>TMANE SELECT
NP_003995.2:p.Gln57Ter
LRG_1350t1:c.169C>T
LRG_1350:g.8563C>T
LRG_1350p1:p.Gln57Ter
NC_000013.10:g.20763552G>A
NM_004004.5:c.169C>T
c.169C>T
p.Gln57*
p.Gln57X

Protein change:

Q57*

Links:

dbSNP: rs111033297

NCBI 1000 Genomes Browser:

rs111033297

Molecular consequence:

NM_004004.6:c.169C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000603833	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (May 19, 2017)	germline	clinical testing	Citation Link,
SCV000841699	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (May 11, 2022)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 21465647, 25087612, 15967879, 16380907, 15547423, 15150777, 26940866, 17041943, 15365987, 21298644, 18324688, 29106882, 25270357, 20553101, 18196482, 31980526, 29625052, 31589614, 10353784, 26467025
SCV001234494	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 26, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10353784, 21465647, 9482292, 16380907, 28492532
SCV001796487	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 5, 2023)	germline	clinical testing	Citation Link

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	germline	unknown	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

Citations

PubMed

Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.

Tabor HK, Auer PL, Jamal SM, Chong JX, Yu JH, Gordon AS, Graubert TA, O'Donnell CJ, Rich SS, Nickerson DA; NHLBI Exome Sequencing Project., Bamshad MJ.

Am J Hum Genet. 2014 Aug 7;95(2):183-93. doi: 10.1016/j.ajhg.2014.07.006. Epub 2014 Jul 31.

PubMed [citation]

PMID:: 25087612
PMCID:: PMC4129409

GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients.

Marlin S, Feldmann D, Blons H, Loundon N, Rouillon I, Albert S, Chauvin P, Garabédian EN, Couderc R, Odent S, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Lemarechal C, Dollfus H, Eliot MM, Delaunoy JL, David A, Calais C, et al.

Arch Otolaryngol Head Neck Surg. 2005 Jun;131(6):481-7.

PubMed [citation]

PMID:: 15967879

See all PubMed Citations (22)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603833.2

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

Description

The p.Gln57Ter (rs111033297) has been observed in several cohorts of patients with sensorineural hearing loss, many carrying a second pathogenic variant in GJB2 (selected references: Wilcox 1999, Snoeckx 2005, Marlin 2005). This variant introduces a premature termination codon and is predicted to result in a truncated protein product. Consistent with a recessive carrier frequency, it is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.004% (identified in 11 out of 276,670 chromosomes). It is also listed in the ClinVar database as pathogenic (Variation ID: 44725). Thus, the p.Gln57Ter variant satisfies our criteria for classification 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 Athena Diagnostics, SCV000841699.2

#	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. The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). In multiple individuals affected with 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 Invitae, SCV001234494.5

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

Description

This sequence change creates a premature translational stop signal (p.Gln57*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 170 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033297, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with clinical features of GJB2-related deafness (PMID: 10353784, 21465647). ClinVar contains an entry for this variant (Variation ID: 44725). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Tyr65*) have been determined to be pathogenic (PMID: 9482292, 16380907). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it 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 GeneDx, SCV001796487.5

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

Description

Nonsense variant predicted to result in protein truncation, as the last 170 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 26940866, 15547423, 18196482, 21298644, 25270357, 9482292, 25087612, 10353784, 21465647, 15150777, 16380907, 11439000, 15070423, 18324688, 20553101, 15365987, 17041943, 29106882, 29625052, 26689913, 31980526, 31589614, 15967879)

#	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: Jun 29, 2024

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