NM_004004.6(GJB2):c.11del (p.Gly4fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 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:: RCV002272297.4

Allele description [Variation Report for NM_004004.6(GJB2):c.11del (p.Gly4fs)]

NM_004004.6(GJB2):c.11del (p.Gly4fs)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.11del (p.Gly4fs)

HGVS:

NC_000013.10:g.20763710del
NC_000013.11:g.20189574del
NG_008358.1:g.8405del
NM_004004.6:c.11delMANE SELECT
NP_003995.2:p.Gly4fs
LRG_1350t1:c.11del
LRG_1350:g.8405del
LRG_1350p1:p.Gly4fs
NC_000013.10:g.20763710del
NC_000013.10:g.20763713del
NC_000013.10:g.20763713delC
NM_004004.5:c.11del
NM_004004.5:c.11delG

Protein change:

G4fs

Links:

dbSNP: rs1555342014

NCBI 1000 Genomes Browser:

rs1555342014

Molecular consequence:

NM_004004.6:c.11del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: indole-3-acetaldehyde oxidase-like isoform X2 [Cucumis melo]
PREDICTED: indole-3-acetaldehyde oxidase-like isoform X2 [Cucumis melo]
gi|659097913|ref|XP_008449878.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002558153	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Feb 1, 2022)	germline	clinical testing	Citation Link,
SCV004295459	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17666888, 23141775, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002558153

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Feb 1, 2022)

germline

clinical testing

Citation Link,

SCV004295459

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2023)

germline

clinical testing

PubMed (3)
[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

A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort.

Putcha GV, Bejjani BA, Bleoo S, Booker JK, Carey JC, Carson N, Das S, Dempsey MA, Gastier-Foster JM, Greinwald JH Jr, Hoffmann ML, Jeng LJ, Kenna MA, Khababa I, Lilley M, Mao R, Muralidharan K, Otani IM, Rehm HL, Schaefer F, Seltzer WK, Spector EB, et al.

Genet Med. 2007 Jul;9(7):413-26.

PubMed [citation]

PMID:: 17666888

A novel p.Leu213X mutation in GJB2 gene in a Portuguese family.

Gonçalves AC, Chora J, Matos TD, Santos R, O'Neill A, Escada P, Fialho G, Caria H.

Int J Pediatr Otorhinolaryngol. 2013 Jan;77(1):89-91. doi: 10.1016/j.ijporl.2012.10.002. Epub 2012 Nov 8.

PubMed [citation]

PMID:: 23141775

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV002558153.2

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

Description

Observed in a patient with hearing loss in published literature; however, no specific information on the patient is available (Putcha GV et al., 2007); Frameshift variant predicted to result in protein truncation, as the last 223 amino acids are replaced with 9 different amino acids, 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: 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, SCV004295459.1

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

Description

This sequence change creates a premature translational stop signal (p.Gly4Alafs*10) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 223 amino acid(s) of the GJB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 17666888). ClinVar contains an entry for this variant (Variation ID: 496214). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Leu213*) have been determined to be pathogenic (PMID: 23141775). 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: Sep 29, 2024

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