NM_004004.6(GJB2):c.231G>A (p.Trp77Ter) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Apr 4, 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:: RCV000018524.40

Allele description [Variation Report for NM_004004.6(GJB2):c.231G>A (p.Trp77Ter)]

NM_004004.6(GJB2):c.231G>A (p.Trp77Ter)

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.231G>A (p.Trp77Ter)

Other names:

p.Trp77Ter

HGVS:

NC_000013.11:g.20189351C>T
NG_008358.1:g.8625G>A
NM_004004.6:c.231G>AMANE SELECT
NP_003995.2:p.Trp77Ter
LRG_1350t1:c.231G>A
LRG_1350:g.8625G>A
LRG_1350p1:p.Trp77Ter
NC_000013.10:g.20763490C>T
c.231G>A
c.231G>A (p.Trp77*)
p.Trp77X

Protein change:

W77*; TRP77TER

Links:

OMIM: 121011.0002; dbSNP: rs80338944

NCBI 1000 Genomes Browser:

rs80338944

Molecular consequence:

NM_004004.6:c.231G>A - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 1A (DFNB1A)
Synonyms:: Deafness nonsyndromic, Connexin 26 linked; Deafness, autosomal recessive 1A; DFNB 1 Nonsyndromic Hearing Loss and Deafness; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009076; MedGen: C2673759; Orphanet: 90636; OMIM: 220290

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LOC130063157 [Homo sapiens]
LOC130063157 [Homo sapiens]
Gene ID:130063157

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038806	OMIM	no assertion criteria provided	Pathogenic (May 1, 1997)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8789457, 9139825
SCV000041041	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (3) [See all records that cite these PMIDs] 16380907, 9328482, 20301449
SCV000917458	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 19, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16380907, 9139825, 18941476, 15617550 Citation Link,
SCV001453344	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV003922397	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004013823	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 33187236, 9139825, 25741868

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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	literature only
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	2	2	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	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

Linkage studies of non-syndromic recessive deafness (NSRD) in a family originating from the Mirpur region of Pakistan maps DFNB1 centromeric to D13S175.

Brown KA, Janjua AH, Karbani G, Parry G, Noble A, Crockford G, Bishop DT, Newton VE, Markham AF, Mueller RF.

Hum Mol Genet. 1996 Jan;5(1):169-73. Erratum in: Hum Mol Genet 1996 May;5(5):710.

PubMed [citation]

PMID:: 8789457

Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations.

Carrasquillo MM, Zlotogora J, Barges S, Chakravarti A.

Hum Mol Genet. 1997 Nov;6(12):2163-72.

PubMed [citation]

PMID:: 9328482

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000038806.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a large consanguineous family of Pakistani origin with recessive nonsyndromic profound deafness (DFNB1A; 220290) that mapped to 13q11-q12 (Brown et al., 1996), Kelsell et al. (1997) found that 2 affected individuals were homozygous for a G-to-A transition in the GJB2 gene, resulting in a trp77-to-ter (W77X) substitution. The parents were heterozygous for the mutation and had no noticeable hearing impairment.

#	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 GeneReviews, SCV000041041.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917458.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: GJB2 c.231G>A (p.Trp77X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 246196 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00015 vs 0.025). c.231G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss in homozygous and compound heterozygous state (e.g. Kelsell 1997, Santos 2005, Mani 2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Natera, Inc., SCV001453344.1

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

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV003922397.1

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

Description

A heterozygous nonsense variant in exon 2 of the GJB2 gene that results in a stop codon and premature truncation of the protein at codon 77 (p.Trp77Ter) was detected. This variant has not been reported in 1000 genomes database and has a minor allele frequency of 0.004%, 0.01%, 0.0008% in the, gnomAD (v3.1), gnomdAD (v2), topmed and databases, respectively. The in silico prediction of the variant is damaging by MuttaionTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

#	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 3billion, SCV004013823.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). The variant is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 33187236). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 33187236). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017001 / PMID: 9139825 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		2	not provided	2	not provided

Last Updated: Nov 3, 2024

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