NM_004004.6(GJB2):c.175G>A (p.Gly59Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 20, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV001851915.9

Allele description [Variation Report for NM_004004.6(GJB2):c.175G>A (p.Gly59Ser)]

NM_004004.6(GJB2):c.175G>A (p.Gly59Ser)

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.175G>A (p.Gly59Ser)

HGVS:

NC_000013.11:g.20189407C>T
NG_008358.1:g.8569G>A
NM_004004.5:c.175G>A
NM_004004.6:c.175G>AMANE SELECT
NP_003995.2:p.Gly59Ser
LRG_1350t1:c.175G>A
LRG_1350:g.8569G>A
LRG_1350p1:p.Gly59Ser
NC_000013.10:g.20763546C>T
P29033:p.Gly59Ser

Protein change:

G59S; GLY59SER

Links:

UniProtKB: P29033#VAR_032751; OMIM: 121011.0035; dbSNP: rs104894410

NCBI 1000 Genomes Browser:

rs104894410

Molecular consequence:

NM_004004.6:c.175G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Ketoconazole
Ketoconazole
Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients.<br/>Year introduced: 1984

MeSH
D007654 (1)
MeSH
B3GNT4 [Papio anubis]
B3GNT4 [Papio anubis]
Gene ID:100999863

Gene
BIM2 BES1-interacting Myc-like protein 2 [Arabidopsis thaliana]
BIM2 BES1-interacting Myc-like protein 2 [Arabidopsis thaliana]
Gene ID:843233

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002237248	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 10, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15952212, 17106596, 30565282, 28492532
SCV003936508	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Dec 20, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002237248

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 10, 2022)

germline

clinical testing

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

SCV003936508

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Dec 20, 2022)

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

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

Connexin 26 (GJB2) mutations in two Swedish patients with atypical Vohwinkel (mutilating keratoderma plus deafness) and KID syndrome both extensively treated with acitretin.

Bondeson ML, Nyström AM, Gunnarsson U, Vahlquist A.

Acta Derm Venereol. 2006;86(6):503-8.

PubMed [citation]

PMID:: 17106596

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002237248.3

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

Description

ClinVar contains an entry for this variant (Variation ID: 17034). For these reasons, this variant has been classified as Pathogenic. 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 missense change has been observed in individuals with Vohwinkel syndrome and Bart‚ÄìPumphrey syndrome (PMID: 15952212, 17106596, 30565282). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 59 of the GJB2 protein (p.Gly59Ser).

#	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, SCV003936508.1

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

Description

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, 21484990, 21933662, 22421650, 19416251, 22547955, 22007731, 22796187, Hsieh2020[casereport], 24011308, 32745176, 15952212, 17106596, 26775130, 30565282)

#	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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