NM_004004.6(GJB2):c.95G>A (p.Arg32His) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Nov 8, 2019
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:: RCV000410025.6

Allele description [Variation Report for NM_004004.6(GJB2):c.95G>A (p.Arg32His)]

NM_004004.6(GJB2):c.95G>A (p.Arg32His)

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.95G>A (p.Arg32His)

HGVS:

NC_000013.11:g.20189487C>T
NG_008358.1:g.8489G>A
NM_004004.6:c.95G>AMANE SELECT
NP_003995.2:p.Arg32His
LRG_1350t1:c.95G>A
LRG_1350:g.8489G>A
LRG_1350p1:p.Arg32His
NC_000013.10:g.20763626C>T
NM_004004.5:c.95G>A
P29033:p.Arg32His
c.95G>A

Protein change:

R32H

Links:

UniProtKB: P29033#VAR_023605; dbSNP: rs111033190

NCBI 1000 Genomes Browser:

rs111033190

Molecular consequence:

NM_004004.6:c.95G>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

Recent activity

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Mus musculus RIKEN cDNA C430048L16 gene (C430048L16Rik), mRNA
Mus musculus RIKEN cDNA C430048L16 gene (C430048L16Rik), mRNA
gi|71067348|ref|NM_198957.1|

Nucleotide
LOC117112148 [Anneissia japonica]
LOC117112148 [Anneissia japonica]
Gene ID:117112148

Gene
LOC110262320 [Sus scrofa]
LOC110262320 [Sus scrofa]
Gene ID:110262320

Gene
LOC110262313 [Sus scrofa]
LOC110262313 [Sus scrofa]
Gene ID:110262313

Gene
ADAP ARIA-interacting double AP2 domain protein [Arabidopsis thaliana]
ADAP ARIA-interacting double AP2 domain protein [Arabidopsis thaliana]
Gene ID:838176

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000487687	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Aug 3, 2016)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 25388846, 15070423, 20863150, 17935238, 16931589, 15617550, 15666300, 11584050, 11493200, 22613756, 15365987 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001360716	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 8, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16380907, 11493200, 11584050, 29196752, 20863150 Citation Link,
SCV001453358	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004047951	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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

Molecular epidemiology of DFNB1 deafness in France.

Roux AF, Pallares-Ruiz N, Vielle A, Faugère V, Templin C, Leprevost D, Artières F, Lina G, Molinari N, Blanchet P, Mondain M, Claustres M.

BMC Med Genet. 2004 Mar 6;5:5.

PubMed [citation]

PMID:: 15070423
PMCID:: PMC385234

See all PubMed Citations (14)

Details of each submission

From Counsyl, SCV000487687.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

#	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, SCV001360716.1

#	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.95G>A (p.Arg32His) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250526 control chromosomes (gnomAD). c.95G>A has been reported in the literature in multiple individuals affected with Non-Syndromic Hearing Loss (e.g. Baux_2017, Marlin_2001, Mustapha_2001, Snoeckx_2005). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant affects gap junction functions by causing impaired membrane targeting and aberrant cellular localization (Xiao_2011). A ClinVar submitter (evaluation after 2014) cites the variant as 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

From Natera, Inc., SCV001453358.1

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

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV004047951.1

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

Description

The GJB2 (c.95G>A) variant has been reported in multiple individuals affected with Deafness, autosomal recessive 1A (Naddafnia et. al., 2019; Roux et. al., 2004). Published functional studies suggest a damaging effect on protein localization as the mutant protein is retained in the endoplasmic reticulum (Xiao et al., 2011). The p.Arg32His variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0004% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Arg32His in GJB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. The amino acid Arg at position 32 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant /CNV in GJB2 gene, the molecular diagnosis is not confirmed.

#	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 26, 2024

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