NM_004004.6(GJB2):c.416G>A (p.Ser139Asn) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Feb 18, 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:: RCV000289146.27

Allele description [Variation Report for NM_004004.6(GJB2):c.416G>A (p.Ser139Asn)]

NM_004004.6(GJB2):c.416G>A (p.Ser139Asn)

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.416G>A (p.Ser139Asn)

HGVS:

NC_000013.11:g.20189166C>T
NG_008358.1:g.8810G>A
NM_004004.6:c.416G>AMANE SELECT
NP_003995.2:p.Ser139Asn
LRG_1350t1:c.416G>A
LRG_1350:g.8810G>A
LRG_1350p1:p.Ser139Asn
NC_000013.10:g.20763305C>T
NM_004004.5:c.416G>A
c.416G>A

Protein change:

S139N

Links:

dbSNP: rs76434661

NCBI 1000 Genomes Browser:

rs76434661

Molecular consequence:

NM_004004.6:c.416G>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
SCV000538032	Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 27, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000599750	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Pathogenic (May 9, 2017)	germline	clinical testing	Citation Link,
SCV000698255	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 18, 2022)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 21465647, 15365987, 16380907, 11493200, 12172394, 19366456, 17666888, 22695344, 24529908, 16864573, 25266519, 15656949, 26778469, 30344259 Citation Link,
SCV000914612	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Oct 22, 2018)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16380907, 17041943, 16864573, 19366456, 21465647, 24529908, 15656949, 11493200, 15365987 Citation Link,
SCV001193789	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Likely pathogenic (Dec 17, 2019)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11493200, 21465647, 25266519, 16950989, 22695344, 20234132, 17041943, 24529908, 12910486, 12925341 Citation Link,
SCV002073945	Center for Molecular Medicine, Children’s Hospital of Fudan University	no assertion criteria provided	Likely pathogenic (Feb 8, 2022)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002086048	Natera, Inc.	no assertion criteria provided	Pathogenic (Feb 12, 2020)	germline	clinical testing
SCV003835740	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 7, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	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

Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing.

Wu BL, Lindeman N, Lip V, Adams A, Amato RS, Cox G, Irons M, Kenna M, Korf B, Raisen J, Platt O.

Genet Med. 2002 Jul-Aug;4(4):279-88.

PubMed [citation]

PMID:: 12172394

A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort.

Putcha GV, Bejjani BA, Bleoo S, Booker JK, Carey JC, Carson N, Das S, Dempsey MA, Gastier-Foster JM, Greinwald JH Jr, Hoffmann ML, Jeng LJ, Kenna MA, Khababa I, Lilley M, Mao R, Muralidharan K, Otani IM, Rehm HL, Schaefer F, Seltzer WK, Spector EB, et al.

Genet Med. 2007 Jul;9(7):413-26.

PubMed [citation]

PMID:: 17666888

See all PubMed Citations (20)

Details of each submission

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538032.2

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

Description

The c.416G>A (p.Ser139Asn) missense variant in the GJB2 gene has been previously reported in at least nine individuals with autosomal recessive Nonsyndromic hearing loss and deafness. This c.416G>A variant has been observed in trans with the well-known 35delG variant in an affected individual (Marlin et al., 2001). An in vitro functional study showed this variant affects localization of the protein (Fleishman et al., 2006). The c.229C>T variant has been reported at low frequency in the c population databases (Exome Sequencing Project [ESP] = 0.0.081%, 1000 Genomes = 0.2%, and ExAC = 0.051%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 5.47; CADD = 24.9; PROVEAN = -2.62), and multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.416G>A (p.Ser139Asn) as a recessive Likely Pathogenic variant for Nonsyndromic hearing loss and deafness.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000599750.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698255.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

Variant summary: GJB2 c.416G>A (p.Ser139Asn) results in a conservative amino acid change located in the Connexin, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251378 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00029 vs 0.025), allowing no conclusion about variant significance. The variant, c.416G>A, has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss in compound heterozygous state with other pathogenic or potentially pathogenic variants (Marlin_2001, Santos_2005, Snoeckx_2005, Dodson_2011, Burke_2016, Plevova_2018). Additionally, it was found to segregate with disease in two affected siblings in a family (Santos_2005). This variant has also been found in hearing loss patients whose second mutation was not identified (Wu_2002, Azaiez_2004, Dai_2009, Bazazzadegan_2012, Bonyadi_2014). These data indicate that the variant is very likely to be associated with disease. Functional studies in HeLa cells showed defective localization and coupling (Fleishman_2006). 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, thirteen have classified as likely pathogenic/pathogenic while one has classified as benign. 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 Illumina Laboratory Services, Illumina, SCV000914612.1

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

Description

Across a selection of the available literature, the c.416G>A (p.Ser139Asn) missense variant has been identified in 13 individuals affected with hearing loss including eight compound heterozygotes (including two siblings), at least five of whom carried another known pathogenic variant in trans and at least six heterozygotes (Marlin et al. 2001; Azaiez et al. 2004; Santos et al. 2005; Snoeckx et al. 2005; Tang et al. 2006; Dai et al. 2009; Dodson et al. 2011; Bonyadi et al. 2014). The p.Ser139Asn variant was absent from 761 controls and is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. Functional studies in HeLa cells transfected with the variant protein showed the p.Ser139Asn variant leads to mislocalization of the protein compared to wild type (Fleishman et al. 2006). Based on the collective evidence, the p.Ser139Asn variant is classified as pathogenic for autosomal recessive non-syndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Myriad Genetics, Inc., SCV001193789.2

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

Description

NM_004004.5(GJB2):c.416G>A(S139N) is classified as likely pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 11493200, 21465647, 25266519, 16950989, 22695344, 20234132, 17041943, 24529908, 12910486 and 12925341. Classification of NM_004004.5(GJB2):c.416G>A(S139N) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	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 Center for Molecular Medicine, Children’s Hospital of Fudan University, SCV002073945.1

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

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

From Natera, Inc., SCV002086048.1

#	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 Baylor Genetics, SCV003835740.1

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

#	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

Last Updated: Nov 3, 2024

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