NM_004004.6(GJB2):c.456C>A (p.Tyr152Ter) AND Autosomal recessive nonsyndromic hearing loss 1A

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Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 12, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003488358.1

Allele description

NM_004004.6(GJB2):c.456C>A (p.Tyr152Ter)

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.456C>A (p.Tyr152Ter)

HGVS:

NC_000013.11:g.20189126G>T
NG_008358.1:g.8850C>A
NM_004004.6:c.456C>AMANE SELECT
NP_003995.2:p.Tyr152Ter
LRG_1350t1:c.456C>A
LRG_1350:g.8850C>A
LRG_1350p1:p.Tyr152Ter
NC_000013.10:g.20763265G>T
NM_004004.5:c.456C>A
c.456C>A
p.Tyr152X

Protein change:

Y152*

Links:

dbSNP: rs111033420

NCBI 1000 Genomes Browser:

rs111033420

Molecular consequence:

NM_004004.6:c.456C>A - nonsense - [Sequence Ontology: SO:0001587]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001339228	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12865758, 19366456, 17666888, 18580690, 26444186 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001339228

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 12, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands.

Pandya A, Arnos KS, Xia XJ, Welch KO, Blanton SH, Friedman TB, Garcia Sanchez G, Liu MD XZ, Morell R, Nance WE.

Genet Med. 2003 Jul-Aug;5(4):295-303.

PubMed [citation]

PMID:: 12865758

GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment.

Dai P, Yu F, Han B, Liu X, Wang G, Li Q, Yuan Y, Liu X, Huang D, Kang D, Zhang X, Yuan H, Yao K, Hao J, He J, He Y, Wang Y, Ye Q, Yu Y, Lin H, Liu L, Deng W, et al.

J Transl Med. 2009 Apr 14;7:26. doi: 10.1186/1479-5876-7-26.

PubMed [citation]

PMID:: 19366456
PMCID:: PMC2679712

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001339228.2

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

Description

Variant summary: GJB2 c.456C>A (p.Tyr152X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251060 control chromosomes (gnomAD). c.456C>A has been reported in the literature, either as a single heterozygous occurrence or in compound heterozygosity with other variants, in multiple individuals affected with hearing loss (e.g. Dai_2009, Pandya_2003, Putcha_2007, Schimmenti_2008, Tayoun_2016). 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. The following publications have been ascertained in the context of this evaluation (PMID: 12865758, 19366456, 17666888, 18580690, 26444186). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; all submitters classified the variant as pathogenic/likely 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

Last Updated: Feb 20, 2024

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