NM_004004.6(GJB2):c.119C>A (p.Ala40Glu) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 18, 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:: RCV001090238.22

Allele description [Variation Report for NM_004004.6(GJB2):c.119C>A (p.Ala40Glu)]

NM_004004.6(GJB2):c.119C>A (p.Ala40Glu)

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.119C>A (p.Ala40Glu)

HGVS:

NC_000013.11:g.20189463G>T
NG_008358.1:g.8513C>A
NM_004004.6:c.119C>AMANE SELECT
NP_003995.2:p.Ala40Glu
LRG_1350t1:c.119C>A
LRG_1350:g.8513C>A
LRG_1350p1:p.Ala40Glu
NC_000013.10:g.20763602G>T
NM_004004.5:c.119C>A
c.119C>A

Protein change:

A40E

Links:

dbSNP: rs111033296

NCBI 1000 Genomes Browser:

rs111033296

Molecular consequence:

NM_004004.6:c.119C>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001245653	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Sep 1, 2019)	germline	clinical testing	Citation Link,
SCV003442049	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 18, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15150777, 15967879, 16380907, 19371219, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001245653

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely pathogenic
(Sep 1, 2019)

germline

clinical testing

Citation Link,

SCV003442049

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 18, 2023)

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	2	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

Large deletion of the GJB6 gene in deaf patients heterozygous for the GJB2 gene mutation: genotypic and phenotypic analysis.

Feldmann D, Denoyelle F, Chauvin P, Garabédian EN, Couderc R, Odent S, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Le Maréchal C, Dollfus H, Eliot MM, Delaunoy JP, David A, Calais C, Drouin-Garraud V, Obstoy MF, Bouccara D, Sterkers O, et al.

Am J Med Genet A. 2004 Jun 15;127A(3):263-7.

PubMed [citation]

PMID:: 15150777

GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients.

Marlin S, Feldmann D, Blons H, Loundon N, Rouillon I, Albert S, Chauvin P, Garabédian EN, Couderc R, Odent S, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Lemarechal C, Dollfus H, Eliot MM, Delaunoy JL, David A, Calais C, et al.

Arch Otolaryngol Head Neck Surg. 2005 Jun;131(6):481-7.

PubMed [citation]

PMID:: 15967879

See all PubMed Citations (5)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001245653.24

#	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	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Invitae, SCV003442049.2

#	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 replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 40 of the GJB2 protein (p.Ala40Glu). This variant is present in population databases (rs111033296, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 15150777, 15967879, 16380907, 19371219). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 44723). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Aug 4, 2024

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