NM_004004.6(GJB2):c.334_335del (p.Lys112fs) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 27, 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:: RCV000517108.12

Allele description [Variation Report for NM_004004.6(GJB2):c.334_335del (p.Lys112fs)]

NM_004004.6(GJB2):c.334_335del (p.Lys112fs)

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.334_335del (p.Lys112fs)

HGVS:

NC_000013.10:g.20763386_20763387del
NC_000013.11:g.20189248_20189249del
NG_008358.1:g.8728_8729del
NM_004004.6:c.334_335delMANE SELECT
NP_003995.2:p.Lys112fs
LRG_1350t1:c.334_335del
LRG_1350:g.8728_8729del
LRG_1350p1:p.Lys112fs
NC_000013.10:g.20763386_20763387del
NC_000013.10:g.20763387_20763388del
NC_000013.10:g.20763387_20763388delTT
NC_000013.11:g.20189248_20189249delTT
NM_004004.5:c.333_334delAA
NM_004004.5:c.334_335delAA
NM_004004.6:c.334_335delAAMANE SELECT
p.Lys112Glufs*2
p.Lys112fs

Protein change:

K112fs

Links:

dbSNP: rs756484720

NCBI 1000 Genomes Browser:

rs756484720

Molecular consequence:

NM_004004.6:c.334_335del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Homo sapiens transmembrane protein 127 (TMEM127), transcript variant 1, mRNA
Homo sapiens transmembrane protein 127 (TMEM127), transcript variant 1, mRNA
gi|305682550|ref|NM_017849.3|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000613513	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 19, 2017)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 9529365, 21465647, 23141775, 12172394, 22695344, 24158611, 27177978, 17666888, 26561413, 25587757, 26467025
SCV001590824	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9529365, 23141775, 9600457, 28492532
SCV001829601	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 27, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000613513

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Jun 19, 2017)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV001590824

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 9, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001829601

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 27, 2024)

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

Vestibular dysfunction in DFNB1 deafness.

Dodson KM, Blanton SH, Welch KO, Norris VW, Nuzzo RL, Wegelin JA, Marin RS, Nance WE, Pandya A, Arnos KS.

Am J Med Genet A. 2011 May;155A(5):993-1000. doi: 10.1002/ajmg.a.33828. Epub 2011 Apr 4.

PubMed [citation]

PMID:: 21465647
PMCID:: PMC3080433

Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing.

Wu BL, Lindeman N, Lip V, Adams A, Amato RS, Cox G, Irons M, Kenna M, Korf B, Raisen J, Platt O.

Genet Med. 2002 Jul-Aug;4(4):279-88.

PubMed [citation]

PMID:: 12172394

See all PubMed Citations (13)

Details of each submission

From Athena Diagnostics, SCV000613513.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

#	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, SCV001590824.4

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

Description

This sequence change creates a premature translational stop signal (p.Lys112Glufs*2) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs756484720, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 9529365, 23141775). It has also been observed to segregate with disease in related individuals. This variant is also known as c.333-334delAA. ClinVar contains an entry for this variant (Variation ID: 189051). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Gln124*) have been determined to be pathogenic (PMID: 9600457). 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, SCV001829601.4

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

Description

Reported in association with hearing loss in additional cases in published literature (PMID: 21465647, 17666888, 26561413); however, patient clinical information limited or not provided; Frameshift variant predicted to result in abnormal protein length as the last 115 amino acids are replaced with 1 different amino acid, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 31215297, 26561413, 27177978, 23141775, 9529365, 26990548, 25587757, 22695344, 17666888, 12172394, 29257206, 27941975, 33096615, 31589614, 34599368, 24158611, 15954104, 21465647)

#	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: Nov 3, 2024

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