NM_004004.6(GJB2):c.176G>T (p.Gly59Val) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 16, 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:: RCV002013660.6

Allele description [Variation Report for NM_004004.6(GJB2):c.176G>T (p.Gly59Val)]

NM_004004.6(GJB2):c.176G>T (p.Gly59Val)

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.176G>T (p.Gly59Val)

HGVS:

NC_000013.11:g.20189406C>A
NG_008358.1:g.8570G>T
NM_004004.5:c.176G>T
NM_004004.6:c.176G>TMANE SELECT
NP_003995.2:p.Gly59Val
LRG_1350t1:c.176G>T
LRG_1350:g.8570G>T
LRG_1350p1:p.Gly59Val
NC_000013.10:g.20763545C>A

Protein change:

G59V

Links:

dbSNP: rs104894404

NCBI 1000 Genomes Browser:

rs104894404

Molecular consequence:

NM_004004.6:c.176G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Homo sapiens chromosome 14 open reading frame 31 (C14orf31), mRNA
Homo sapiens chromosome 14 open reading frame 31 (C14orf31), mRNA
gi|22748720|ref|NM_152330.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002305872	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 8, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10633135, 15952212, 17106596, 30565282, 16300957, 15146474, 17671735, 28492532
SCV005325948	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 16, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002305872

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 8, 2022)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV005325948

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Nov 16, 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

Citations

PubMed

A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350).

Heathcote K, Syrris P, Carter ND, Patton MA.

J Med Genet. 2000 Jan;37(1):50-1.

PubMed [citation]

PMID:: 10633135
PMCID:: PMC1734451

G59S mutation in the GJB2 (connexin 26) gene in a patient with Bart-Pumphrey syndrome.

Alexandrino F, Sartorato EL, Marques-de-Faria AP, Steiner CE.

Am J Med Genet A. 2005 Jul 30;136(3):282-4. No abstract available.

PubMed [citation]

PMID:: 15952212

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002305872.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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. This variant disrupts the p.Gly59 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic for autosomal dominant GJB2-related conditions (PMID: 10633135, 15952212, 17106596, 30565282). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GJB2 function (PMID: 16300957). This variant is also known as c.177G>T. This missense change has been observed in individual(s) with deafness (PMID: 15146474, 17671735). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 59 of the GJB2 protein (p.Gly59Val).

#	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, SCV005325948.1

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

Description

Published functional studies demonstrate a damaging effect on channel function by reducing channel activation (PMID: 16300957); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25388846, 15146474, 16300957)

#	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: Oct 8, 2024

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