NM_004004.6(GJB2):c.239A>C (p.Gln80Pro) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jul 17, 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:: RCV001288584.8

Allele description [Variation Report for NM_004004.6(GJB2):c.239A>C (p.Gln80Pro)]

NM_004004.6(GJB2):c.239A>C (p.Gln80Pro)

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.239A>C (p.Gln80Pro)

HGVS:

NC_000013.11:g.20189343T>G
NG_008358.1:g.8633A>C
NM_004004.6:c.239A>CMANE SELECT
NP_003995.2:p.Gln80Pro
LRG_1350t1:c.239A>C
LRG_1350:g.8633A>C
LRG_1350p1:p.Gln80Pro
NC_000013.10:g.20763482T>G
NM_004004.5:c.239A>C

Protein change:

Q80P

Links:

dbSNP: rs727504302

NCBI 1000 Genomes Browser:

rs727504302

Molecular consequence:

NM_004004.6:c.239A>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001475810	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Mar 18, 2020)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 30094485, 25388846, 21738759, 16380907, 25447126, 17666888, 16532460, 12325027, 26467025
SCV001580693	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16532460, 30094485, 15855033, 30473554, 28492532
SCV003927452	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (May 11, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001475810

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Likely pathogenic
(Mar 18, 2020)

unknown

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001580693

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 17, 2023)

germline

clinical testing

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

SCV003927452

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(May 11, 2023)

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Bioinformatic Analysis of GJB2 Gene Missense Mutations.

Yilmaz A.

Cell Biochem Biophys. 2015 Apr;71(3):1623-42. doi: 10.1007/s12013-014-0385-7.

PubMed [citation]

PMID:: 25388846

Allele-specific impairment of GJB2 expression by GJB6 deletion del(GJB6-D13S1854).

Rodriguez-Paris J, Tamayo ML, Gelvez N, Schrijver I.

PLoS One. 2011;6(6):e21665. doi: 10.1371/journal.pone.0021665. Epub 2011 Jun 29.

PubMed [citation]

PMID:: 21738759
PMCID:: PMC3126855

See all PubMed Citations (12)

Details of each submission

From Athena Diagnostics, SCV001475810.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Statistically enriched in uncharacterized patients vs. unmatched population data. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001580693.4

#	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 replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 80 of the GJB2 protein (p.Gln80Pro). This variant is present in population databases (rs727504302, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 16532460, 30094485). ClinVar contains an entry for this variant (Variation ID: 177735). 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. This variant disrupts the p.Gln80 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15855033, 30473554). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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, SCV003927452.1

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

Description

Observed in unrelated patients with hearing loss in published literature, but additional information about genotype and phenotype is not available (Snoeckx et al., 2005; Putcha et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30094485, 12325027, 25388846, 17666888, 21738759, 16532460, 31160754, 16380907)

#	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: Sep 29, 2024

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