NM_004004.6(GJB2):c.132G>A (p.Trp44Ter) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 20, 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:: RCV000593364.26

Allele description [Variation Report for NM_004004.6(GJB2):c.132G>A (p.Trp44Ter)]

NM_004004.6(GJB2):c.132G>A (p.Trp44Ter)

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.132G>A (p.Trp44Ter)

HGVS:

NC_000013.11:g.20189450C>T
NG_008358.1:g.8526G>A
NM_004004.6:c.132G>AMANE SELECT
NP_003995.2:p.Trp44Ter
LRG_1350t1:c.132G>A
LRG_1350:g.8526G>A
LRG_1350p1:p.Trp44Ter
NC_000013.10:g.20763589C>T
NM_004004.5:c.132G>A
p.Trp44*

Protein change:

W44*

Links:

dbSNP: rs104894407

NCBI 1000 Genomes Browser:

rs104894407

Molecular consequence:

NM_004004.6:c.132G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000700809	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 16, 2016)	germline	clinical testing	Citation Link,
SCV000883945	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (May 9, 2017)	germline	clinical testing	Citation Link,
SCV000933879	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 20, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 10376574, 15070423, 26346709, 26553399, 15967879, 16380907, 21465647, 22695344, 24158611, 28492532
SCV001168433	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 5, 2021)	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

Citations

PubMed

Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness.

Green GE, Scott DA, McDonald JM, Woodworth GG, Sheffield VC, Smith RJ.

JAMA. 1999 Jun 16;281(23):2211-6.

PubMed [citation]

PMID:: 10376574

Molecular epidemiology of DFNB1 deafness in France.

Roux AF, Pallares-Ruiz N, Vielle A, Faugère V, Templin C, Leprevost D, Artières F, Lina G, Molinari N, Blanchet P, Mondain M, Claustres M.

BMC Med Genet. 2004 Mar 6;5:5.

PubMed [citation]

PMID:: 15070423
PMCID:: PMC385234

See all PubMed Citations (10)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000700809.2

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883945.1

#	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.132G>A; p.Trp44Ter variant (rs104894407) has been reported in the literature in individuals with hearing loss who carried a pathogenic variant on the opposite chromosome (Green 1999, Martinez-Saucedo 2015, Roux 2004). It is reported in ClinVar (Variation ID: 158605), and observed in the general population databases at a frequency of 0.003 percent (8/276604 alleles; Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript, and is considered pathogenic. REFERENCES Link to ClinVar database for p.Trp44Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/158605/ Green GE et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Martinez-Saucedo M et al. Two novel compound heterozygous families with a trimutation in the GJB2 gene causing sensorineural hearing loss. Int J Pediatr Otorhinolaryngol. 2015 Dec;79(12):2295-9. Roux AF et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004 Mar 6;5:5.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000933879.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change creates a premature translational stop signal (p.Trp44*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894407, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 10376574, 15070423, 26346709, 26553399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 158605). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Leu56Argfs*26) have been determined to be pathogenic (PMID: 15967879, 16380907, 21465647, 22695344, 24158611). 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, SCV001168433.3

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

Description

Observed with a pathogenic variant in additional unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Green et al., 1999; Roux et al., 2004; Angeli et al., 2008); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 183 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 17666888, 26553399, 18758381, 10376574, 31589614, 15070423, 26346709, 17041943, 34440441)

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine