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

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Apr 8, 2022
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:: RCV000210857.4

Allele description [Variation Report for NM_004004.6(GJB2):c.598G>A (p.Gly200Arg)]

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]

Observations:

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
SCV000267104	Institut Pasteur du Maroc	no assertion criteria provided	Pathogenic (Apr 1, 2016)	inherited	clinical testing
SCV000487490	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jan 21, 2016)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19567088, 23967136, 22567861, 24949729, 22695344, 21094084 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
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

SCV000267104

Institut Pasteur du Maroc

no assertion criteria provided

Pathogenic
(Apr 1, 2016)

inherited

clinical testing

SCV000487490

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Jan 21, 2016)

unknown

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

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
	inherited	yes	1	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

The spectrum of GJB2 mutations in the Iranian population with non-syndromic hearing loss--a twelve year study.

Bazazzadegan N, Nikzat N, Fattahi Z, Nishimura C, Meyer N, Sahraian S, Jamali P, Babanejad M, Kashef A, Yazdan H, Sabbagh Kermani F, Taghdiri M, Azadeh B, Mojahedi F, Khoshaeen A, Habibi H, Reyhanifar F, Nouri N, Smith RJ, Kahrizi K, Najmabadi H.

Int J Pediatr Otorhinolaryngol. 2012 Aug;76(8):1164-74. doi: 10.1016/j.ijporl.2012.04.026. Epub 2012 Jun 12.

PubMed [citation]

PMID:: 22695344

Multiple effects of childhood deafness on cortical activity in children receiving bilateral cochlear implants simultaneously.

Gordon KA, Tanaka S, Wong DD, Stockley T, Ramsden JD, Brown T, Jewell S, Papsin BC.

Clin Neurophysiol. 2011 Apr;122(4):823-33. doi: 10.1016/j.clinph.2010.10.037. Epub 2010 Nov 19.

PubMed [citation]

PMID:: 21094084

See all PubMed Citations (7)

Details of each submission

From Institut Pasteur du Maroc, SCV000267104.1

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

Description

Pathogenic

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

From Counsyl, SCV000487490.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	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 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: Oct 26, 2024

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