NM_004004.6(GJB2):c.283G>A (p.Val95Met) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Apr 27, 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:: RCV000037834.11

Allele description [Variation Report for NM_004004.6(GJB2):c.283G>A (p.Val95Met)]

NM_004004.6(GJB2):c.283G>A (p.Val95Met)

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.283G>A (p.Val95Met)

HGVS:

NC_000013.11:g.20189299C>T
NG_008358.1:g.8677G>A
NM_004004.6:c.283G>AMANE SELECT
NP_003995.2:p.Val95Met
LRG_1350t1:c.283G>A
LRG_1350:g.8677G>A
LRG_1350p1:p.Val95Met
NC_000013.10:g.20763438C>T
NM_004004.5:c.283G>A
P29033:p.Val95Met
c.283G>A
p.VAL95MET

Protein change:

V95M

Links:

UniProtKB: P29033#VAR_002144; dbSNP: rs111033299

NCBI 1000 Genomes Browser:

rs111033299

Molecular consequence:

NM_004004.6:c.283G>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

Recent activity

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Scedosporium apiospermum uncharacterized protein (SAPIO_CDS1124), partial mRNA
Scedosporium apiospermum uncharacterized protein (SAPIO_CDS1124), partial mRNA
gi|1027059153|ref|XM_016784478.1|

Nucleotide
Scedosporium apiospermum uncharacterized protein (SAPIO_CDS1093), partial mRNA
Scedosporium apiospermum uncharacterized protein (SAPIO_CDS1093), partial mRNA
gi|1027059103|ref|XM_016784453.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220868	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Nov 7, 2014)	unknown	literature only	PubMed (10) [See all records that cite these PMIDs] 15967879, 12562518, 14985372, 9529365, 16380907, 12081719, 16217030, 16222667, 12239718, 12865758 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001761051	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Jul 10, 2020)	inherited	clinical testing	Citation Link,
SCV002086055	Natera, Inc.	no assertion criteria provided	Pathogenic (Apr 29, 2020)	germline	clinical testing
SCV002511670	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 27, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9529365, 14985372, 12865758, 16222667, 24158611, 12081719, 21481246, 16217030, 23503914 Citation Link

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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
not provided	inherited	unknown	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients.

Marlin S, Feldmann D, Blons H, Loundon N, Rouillon I, Albert S, Chauvin P, Garabédian EN, Couderc R, Odent S, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Lemarechal C, Dollfus H, Eliot MM, Delaunoy JL, David A, Calais C, et al.

Arch Otolaryngol Head Neck Surg. 2005 Jun;131(6):481-7.

PubMed [citation]

PMID:: 15967879

Functional analysis of connexin-26 mutants associated with hereditary recessive deafness.

Wang HL, Chang WT, Li AH, Yeh TH, Wu CY, Chen MS, Huang PC.

J Neurochem. 2003 Feb;84(4):735-42.

PubMed [citation]

PMID:: 12562518

See all PubMed Citations (13)

Details of each submission

From Counsyl, SCV000220868.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (10)

#	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 New York Genome Center - CSER-NYCKidSeq, SCV001761051.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	inherited	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Natera, Inc., SCV002086055.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511670.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: GJB2 c.283G>A (p.Val95Met) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251540 control chromosomes (gnomAD, Cheng_2005, Kelley_1998). This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.8e-05 vs 0.025), allowing no conclusion about variant significance. c.283G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Castro_2013, Cheng_2005, Cryns_2004, Kelley_1998, Dalamon_2013). These data indicate that the variant is very likely to be associated with disease. One publication reports that the variant negatively impacted large molecule trafficking across gap junctions, thereby disrupting gap junction mediated intracellular signaling (Zhang_2005). Nine ClinVar submitters have assessed the variant since 2014: all have classified 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

Last Updated: Nov 3, 2024

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