NM_004004.6(GJB2):c.456C>A (p.Tyr152Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 8, 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:: RCV000578957.10

Allele description [Variation Report for NM_004004.6(GJB2):c.456C>A (p.Tyr152Ter)]

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000680740	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 8, 2024)	germline	clinical testing	Citation Link,
SCV001405519	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19366456, 9529365, 12910486, 20863150, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000680740

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jul 8, 2024)

germline

clinical testing

Citation Link,

SCV001405519

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 11, 2024)

germline

clinical testing

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

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

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

Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss.

Kelley PM, Harris DJ, Comer BC, Askew JW, Fowler T, Smith SD, Kimberling WJ.

Am J Hum Genet. 1998 Apr;62(4):792-9.

PubMed [citation]

PMID:: 9529365
PMCID:: PMC1377046

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000680740.7

#	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 75 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12865758, 18580690, 19366456, 26444186, 19081147, 36048236, 17666888)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001405519.4

#	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.Tyr152*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033420, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 19366456). ClinVar contains an entry for this variant (Variation ID: 44753). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). 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

Last Updated: Nov 3, 2024

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