NM_004004.6(GJB2):c.598G>A (p.Gly200Arg) AND Autosomal recessive nonsyndromic hearing loss 1A

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Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 8, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002229191.1

Allele description

NM_004004.6(GJB2):c.598G>A (p.Gly200Arg)

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.598G>A (p.Gly200Arg)

HGVS:

NC_000013.11:g.20188984C>T
NG_008358.1:g.8992G>A
NM_004004.6:c.598G>AMANE SELECT
NP_003995.2:p.Gly200Arg
LRG_1350t1:c.598G>A
LRG_1350:g.8992G>A
LRG_1350p1:p.Gly200Arg
NC_000013.10:g.20763123C>T
NM_004004.5:c.598G>A

Protein change:

G200R

Links:

dbSNP: rs786204597

NCBI 1000 Genomes Browser:

rs786204597

Molecular consequence:

NM_004004.6:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 1A (DFNB1A)
Synonyms:: Deafness nonsyndromic, Connexin 26 linked; Deafness, autosomal recessive 1A; DFNB 1 Nonsyndromic Hearing Loss and Deafness; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009076; MedGen: C2673759; Orphanet: 90636; OMIM: 220290

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002511671	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 8, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22567861, 23967136, 24949729, 27169813, 19567088 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002511671

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 8, 2022)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

[Changes in the connexin 26 (GJB2) gene in Russian patients with hearing disorders: results of long-term molecular diagnostics of hereditary nonsyndromic deafness].

Bliznets EA, Galkina VA, Matiushchenko GN, Kisina AG, Markova TG, Poliakov AV.

Genetika. 2012 Jan;48(1):112-24. Russian.

PubMed [citation]

PMID:: 22567861

Analysis of trafficking, stability and function of human connexin 26 gap junction channels with deafness-causing mutations in the fourth transmembrane helix.

Ambrosi C, Walker AE, Depriest AD, Cone AC, Lu C, Badger J, Skerrett IM, Sosinsky GE.

PLoS One. 2013;8(8):e70916. doi: 10.1371/journal.pone.0070916.

PubMed [citation]

PMID:: 23967136
PMCID:: PMC3744544

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511671.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: GJB2 c.598G>A (p.Gly200Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251254 control chromosomes. c.598G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals from diverse ethnicities affected with Autosomal Recessive Non-Syndromic Hearing Loss (example, Liu_2009, Bliznets_2012, Chaleshtori_2005, Shafique_2014, Bakhchane_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating improper trafficking with intracellular aggregation (Ambrosi_2013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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: Feb 20, 2024

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