NM_004004.6(GJB2):c.508_511dup (p.Ala171fs) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 14, 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:: RCV000498375.16

Allele description [Variation Report for NM_004004.6(GJB2):c.508_511dup (p.Ala171fs)]

NM_004004.6(GJB2):c.508_511dup (p.Ala171fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.508_511dup (p.Ala171fs)

HGVS:

NC_000013.11:g.20189071_20189074dup
NG_008358.1:g.8902_8905dup
NM_004004.6:c.508_511dupMANE SELECT
NP_003995.2:p.Ala171fs
LRG_1350t1:c.508_511dup
LRG_1350:g.8902_8905dup
LRG_1350p1:p.Ala171fs
NC_000013.10:g.20763209_20763210insCGTT
NC_000013.10:g.20763210_20763213dup
NC_000013.11:g.20189070_20189071insCGTT
NM_004004.5:c.508_511dupAACG
NM_004004.6:c.508_511dup
NM_004004.6:c.508_511dupAACGMANE SELECT
p.Ala171Glufs*40

Protein change:

A171fs

Links:

dbSNP: rs773528125

NCBI 1000 Genomes Browser:

rs773528125

Molecular consequence:

NM_004004.6:c.508_511dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000589636	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 19, 2022)	germline	clinical testing	Citation Link,
SCV000701343	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Jul 20, 2016)	germline	clinical testing	Citation Link,
SCV001225144	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 14, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12172394, 25891447, 9529365, 12910486, 20863150, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000589636

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 19, 2022)

germline

clinical testing

Citation Link,

SCV000701343

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Pathogenic
(Jul 20, 2016)

germline

clinical testing

Citation Link,

SCV001225144

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 14, 2023)

germline

clinical testing

PubMed (6)
[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	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

The deafness-causing mutation c.508_511dup in the GJB2 gene and a literature review.

Zhu YM, Li Y, Wang YL, Bian PP, Xu BC, Liu XW, Chen XJ, Liu F, Guo YF, Wang QJ.

Acta Otolaryngol. 2015 Sep;135(9):914-8. doi: 10.3109/00016489.2015.1035796. Epub 2015 Apr 20. Review.

PubMed [citation]

PMID:: 25891447

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000589636.5

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

Description

Frameshift variant predicted to result in protein truncation, as the last 56 amino acids are lost and replaced with 39 incorrect amino acids (HGMD); This variant is associated with the following publications: (PMID: 24737404, 12172394, 16712961, 25587757, 26004784, 27247933, 27792752, 26783197, 17444514, 25891447, 24256046, 23638949, 22335977, 22695344, 28717060, 29926981, 31160754, 29871260)

#	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 Eurofins Ntd Llc (ga), SCV000701343.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001225144.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Ala171Glufs*40) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs773528125, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 12172394, 25891447). This variant is also known as 511-512insAACG. ClinVar contains an entry for this variant (Variation ID: 189070). 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 24, 2024

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