NM_004004.6(GJB2):c.551G>C (p.Arg184Pro) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Oct 18, 2018
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:: RCV000018531.50

Allele description [Variation Report for NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)]

NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)

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.551G>C (p.Arg184Pro)

HGVS:

NC_000013.11:g.20189031C>G
NG_008358.1:g.8945G>C
NM_004004.6:c.551G>CMANE SELECT
NP_003995.2:p.Arg184Pro
LRG_1350t1:c.551G>C
LRG_1350:g.8945G>C
LRG_1350p1:p.Arg184Pro
NC_000013.10:g.20763170C>G
NM_004004.5:c.551G>C
P29033:p.Arg184Pro
c.551G>C
c.551G>C (p.Arg184Pro)

Protein change:

R184P; ARG184PRO

Links:

UniProtKB: P29033#VAR_015943; OMIM: 121011.0008; dbSNP: rs80338950

NCBI 1000 Genomes Browser:

rs80338950

Molecular consequence:

NM_004004.6:c.551G>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

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
SCV000038813	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2004)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9620796, 14735592
SCV000041050	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 14735592, 16380907, 9336442, 20301449
SCV000220825	Counsyl	no assertion criteria provided	Pathogenic (Sep 9, 2016)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 17935238, 12505163, 12176179, 12189493, 17666888, 18941476, 18560174, 9336442, 10544226, 21465647, 22975760
SCV000599760	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,
SCV000698267	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 23, 2016)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 9336442, 10544226, 24529908, 18941476, 21465647, 12189493, 26117665, 21198395, 25708704, 26381000, 16380907, 10982180 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000914611	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Oct 18, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21465647, 25708704, 17041943, 10544226, 18941476, 12505163, 12189493, 15365987 Citation Link,
SCV002094996	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 12, 2020)	germline	clinical testing

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	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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Connexin 26 gene linked to a dominant deafness.

Denoyelle F, Lina-Granade G, Plauchu H, Bruzzone R, Chaïb H, Lévi-Acobas F, Weil D, Petit C.

Nature. 1998 May 28;393(6683):319-20. No abstract available.

PubMed [citation]

PMID:: 9620796

Maternal origin of a de novo mutation of the connexin 26 gene resulting in recessive nonsyndromic deafness.

Shalev SA, Hujirat Y.

Am J Med Genet A. 2004 Feb 1;124A(4):411-2. No abstract available.

PubMed [citation]

PMID:: 14735592

See all PubMed Citations (23)

Details of each submission

From OMIM, SCV000038813.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

For discussion of the arg184-to-pro (R184P) mutation in the GJB2 gene that was found in compound heterozygous state in 2 sisters with autosomal recessive deafness (DFNB1A; 220290) by Denoyelle et al. (1997), see 121011.0007.

In an 18-month-old Arab Israeli boy with nonsyndromic hearing impairment, Shalev and Hujirat (2004) screened the GJB2 gene for mutations known to occur in the Arab population and identified the 35delG (121011.0005) and R184P mutations. The father was a carrier of 35delG and the mother was negative for both mutations; however, biparental contribution was confirmed by segregation analysis. Shalev and Hujirat (2004) stated that this case represented the first report of a de novo mutation in the GJB2 gene leading to recessive nonsyndromic hearing impairment, and was particularly unusual because the new mutation occurred on the maternal allele.

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

From GeneReviews, SCV000041050.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

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

From Counsyl, SCV000220825.2

#	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 Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000599760.1

#	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, SCV000698267.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

Variant summary: Variant affects a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and hydrophobic Proline (P). 5/5 in silico tools predict the variant to be disease causing. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00412% which does not exceed the maximal expected allele frequency of a disease causing GJB2 allele (2.5%). The variant was reported in several patients affected with hearing loss, most of them were homozygous for the variant of interest or compound heterozygotes with another pathogenic GJB2 mutation indicating pathogenicity. A functional study demonstrated R184P as a coupling deficient variant. In experiments with oligomerization of mutated connexin proteins R184P was detected only as monomeric protein, suggesting inability to form hemichannels further supporting pathogenicity. Additionally, several clinical diagnostic laboratories and reputable database classify variant as pathogenic (without evidence to independently evaluate). Furthermore, variants affecting the same codon, p.R184W, p.R184G and p.R184Q were reported to be associated with Deafness, autosomal recessive 1 and Deafness, autosomal dominant 3, respectively indicating the variant to be located in a mutational hotspot and the Arg184 residue to be functionally important. Considering all evidence, the variant was classified as a 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, SCV000914611.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Across a selection of the available literature, GJB2 the c.551G>C (p.Arg184Pro) missense variant has been identified in a sixteen individuals affected with hearing loss including three homozygotes, ten compound heterozygotes, and three heterozygotes (Murgia et al. 1999; Azaiez et al. 2004; Tang et al. 2006; Mani et al. 2009; Dodson et al. 2011; Keivani et al. 2015). The variant was also identified in six unaffected heterozygotes (Keivani et al. 2015). The p.Arg184Pro variant was absent from 355 controls but is reported at a frequency of 0.000087 in the Latino population of the Genome Aggregation Database. In vitro functional studies in HeLa cells showed that the p.Arg184Pro variant resulted in defective trafficking, exhibited increased RNA expression versus wild type and resulted in a coupling defect (Mani et al. 2009; ThÃ¶nnissen et al. 2002). In Xenopus oocytes the variant protein was unable to induce formation of intracellular channels thus resulting in a loss of function (Bruzzone et al. 2003). Based on the collective evidence, the p.Arg184Pro variant is classified as pathogenic for autosomal recessive nonsyndromic 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 Natera, Inc., SCV002094996.1

#	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

Last Updated: May 1, 2024

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