NM_004004.6(GJB2):c.617A>G (p.Asn206Ser) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 5, 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:: RCV000037868.23

Allele description [Variation Report for NM_004004.6(GJB2):c.617A>G (p.Asn206Ser)]

NM_004004.6(GJB2):c.617A>G (p.Asn206Ser)

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.617A>G (p.Asn206Ser)

HGVS:

NC_000013.11:g.20188965T>C
NG_008358.1:g.9011A>G
NM_004004.6:c.617A>GMANE SELECT
NP_003995.2:p.Asn206Ser
LRG_1350t1:c.617A>G
LRG_1350:g.9011A>G
LRG_1350p1:p.Asn206Ser
NC_000013.10:g.20763104T>C
NM_004004.5:c.617A>G
c.617A>G

Protein change:

N206S

Links:

dbSNP: rs111033294

NCBI 1000 Genomes Browser:

rs111033294

Molecular consequence:

NM_004004.6:c.617A>G - 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
SCV000698269	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 10, 2017)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 23668481, 23967136, 22796187, 15070423, 11493200, 15967879, 16380907, 18684989, 12172394, 11556849 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001193901	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Jan 3, 2020)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15070423, 14985372, 15967879, 12172394, 11493200 Citation Link,
SCV001463360	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002061212	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 23668481, 16380907, 17666888, 15967879, 12172394, 18684989, 15241677, 16864573, 23967136, 23328711, 25741868

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
not provided	germline	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 role of connexins in ear and skin physiology - functional insights from disease-associated mutations.

Xu J, Nicholson BJ.

Biochim Biophys Acta. 2013 Jan;1828(1):167-78. doi: 10.1016/j.bbamem.2012.06.024. Epub 2012 Jul 13. Review.

PubMed [citation]

PMID:: 22796187
PMCID:: PMC3521577

Connexin 26 studies in patients with sensorineural hearing loss.

Kenna MA, Wu BL, Cotanche DA, Korf BR, Rehm HL.

Arch Otolaryngol Head Neck Surg. 2001 Sep;127(9):1037-42.

PubMed [citation]

PMID:: 11556849

See all PubMed Citations (16)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698269.1

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

Description

Variant summary: The GJB2 c.617A>G (p.Asn206Ser) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 10/119604 control chromosomes at a frequency of 0.0000836, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported in many affected individuals both as homozygotes and compound heterozygotes. Functional studies showed the variant to result in channel malfunction with normal trafficking (Ambros_PNAS_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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 Myriad Genetics, Inc., SCV001193901.2

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

Description

NM_004004.5(GJB2):c.617A>G(N206S) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID: 15070423, 14985372, 15967879, 12172394 and 11493200. Classification of NM_004004.5(GJB2):c.617A>G(N206S) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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 Natera, Inc., SCV001463360.1

#	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 DASA, SCV002061212.1

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

Description

The c.617A>G;p.(Asn206Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 44763; PMID: 23668481; 16380907; 17666888; 15967879; 12172394) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 18684989, 15241677, 16864573, 23967136) - PS3_moderate. The variant is present at low allele frequencies population databases (rs111033294– gnomAD 0.001840%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Asn206Ser) was detected in trans with a pathogenic variant (PMID: 23668481; 16380907; 17666888; 15967879; 12172394) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic.

#	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		1	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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