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

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Jan 20, 2026
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:: RCV000018531.60

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

Molecular consequence:

NM_004004.6:c.551G>C - 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; Nonsyndromic Hearing Loss and Deafness, DFNB1; 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.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Pathogenic (Jun 8, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV005400139	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 20, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12792423, 20301449, 26096904, 28428247, 31160754, 31569309, 36672810, 25741868
SCV007610625	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 20, 2026)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12505163, 10544226, 10830906, 18941476, 25741868

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	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
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

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 (32)

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, SCV000220825.3

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

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

#	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., SCV002094996.2

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

Description

The c.551G>C variant in GJB2 is a missense variant predicted to cause substitution of arginine to proline at amino acid 184. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 22695344). A different variant at the same position has been determined to be Pathogenic or Likely Pathogenic. Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, 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 Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV004809807.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005400139.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (PMID: 20301449). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (17 heterozygotes, 0 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygote, 0 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0704 – Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg184Trp) has previously been classified as pathogenic in ClinVar and the Deafness Variation db. This variant has also been identified in 4 individuals with hearing loss, 3 of which were identified with another pathogenic variant, and 1 in a heterozygous state (PMID:26096904). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in many individuals with hearing loss and with other pathogenic variants (ClinVar, Deafness Variation db, PMID:36672810, PMID: 31569309). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

From 3billion, SCV007610625.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12505163, 18941476). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017007 /PMID: 10544226). Different missense changes at the same codon (p.Arg184Gln, p.Arg184Gly, p.Arg184Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029662, VCV000560669, VCV004535899 /PMID: 10830906, 11439000, 12497637 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004809807	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004809807

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 4, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: Jul 14, 2026

Relating variation to medicine