NM_004004.6(GJB2):c.551G>C (p.Arg184Pro) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 15, 2025
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:: RCV000657913.29

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]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000779679	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 7, 2022)	germline	clinical testing	Citation Link,
SCV000885514	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Nov 25, 2020)	germline	clinical testing	Citation Link,
SCV000935561	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 15, 2025)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 10874298, 19371219, 25708704, 26117665, 12176036, 12189493, 12505163, 15241677, 18941476, 28492532
SCV001476380	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jul 23, 2020)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 10544226, 18941476, 12505163, 21465647, 25708704, 12189493, 26117665, 26381000, 25085637, 24529908, 19715472, 19173109, 19125024, 18560174, 17935238, 17666888, 17485979, 31992338, 31620696, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation analysis of the GJB2 (connexin 26) gene by DGGE in Greek patients with sensorineural deafness.

Antoniadi T, Grønskov K, Sand A, Pampanos A, Brøndum-Nielsen K, Petersen MB.

Hum Mutat. 2000;16(1):7-12.

PubMed [citation]

PMID:: 10874298

Analysis of the GJB2 and GJB6 genes in Italian patients with nonsyndromic hearing loss: frequencies, novel mutations, genotypes, and degree of hearing loss.

Primignani P, Trotta L, Castorina P, Lalatta F, Sironi F, Radaelli C, Degiorgio D, Curcio C, Travi M, Ambrosetti U, Cesarani A, Garavelli L, Formigoni P, Milani D, Murri A, Cuda D, Coviello DA.

Genet Test Mol Biomarkers. 2009 Apr;13(2):209-17. doi: 10.1089/gtmb.2008.0086.

PubMed [citation]

PMID:: 19371219

See all PubMed Citations (25)

Details of each submission

From GeneDx, SCV000779679.4

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

Description

Published functional studies demonstrate a damaging effect; variant results in the failure of intracellular coupling and gap junction channel formation (Thnnissen et al., 2002; Bruzzone et al., 2003); A different missense change at this residue (p.(R184W) has been reported as pathogenic in the published literature and at GeneDxin association with autosomal recessive GJB2-related hearing loss (Wilcox et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24529908, 15967879, 17485979, 12176179, 11551103, 22808909, 15666300, 9336442, 15855033, 12417772, 19173109, 15365987, 19715472, 19941053, 18560174, 19371219, 19125024, 14985372, 26381000, 17935238, 16380907, 21465647, 18941476, 12505163, 22975760, 10544226, 25388846, 26117665, 25085637, 17666888, 31980526, 32300592, 12176036, 34426522, 33096615, 31589614, 32067424, 10874298, 12189493, 25708704, 17041943, 27535533, 24158611, 10982180, 10830906)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885514.4

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

Description

The GJB2 c.551G>C; p.Arg184Pro variant (rs80338950) has been described in a homozygous or compound heterozygous state in several individuals and families with nonsyndomic hearing loss (Denoyelle 1997, Dodson 2011, Keivani 2015). In addition, functional assays suggest that this variant impairs membrane trafficking, intercellular coupling, and hemichannel formation (Bruzzone 2003, Mani 2009, Thonnissen 2002). This variant is reported as pathogenic in ClinVar (Variation ID: 17007), and is observed in the general population at a low allele frequency of 0.006% (17/282684 alleles) in the Genome Aggregation Database. The arginine at codon 184 is highly conserved, and computational algorithms (SIFT, PolyPhen2) predict this variant to be damaging to the protein. Additionally, other amino acid substitutions at this codon (Gln, Gly, Trp) have been reported in individuals with hearing loss and are considered disease-causing (Pang 2014, Wang 2000, Zoll 2003). Based on the above information, p.Arg184Pro is considered pathogenic for autosomal recessive hearing loss. References: Bruzzone R et al. Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett. 2003 Jan 2;533(1-3):79-88. Denoyelle F et al. Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet. 1997 Nov;6(12):2173-7. Dodson KM et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011 May;155A(5):993-1000. Keivani A et al. A new compound heterozygous mutation in GJB2 causes nonsyndromic hearing loss in a consanguineous Iranian family. Int J Pediatr Otorhinolaryngol. 2015 Apr;79(4):553-6. Mani RS et al. Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss. Eur J Hum Genet. 2009 Apr;17(4):502-9. Pang X et al. Characterization of spectrum, de novo rate and genotype-phenotype correlation of dominant GJB2 mutations in Chinese hans. PLoS One. 2014 Jun 19;9(6):e100483. Thonnissen E et al. Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. Hum Genet. 2002 Aug;111(2):190-7. Wilcox SA et al. High frequency hearing loss correlated with mutations in the GJB2 gene. Hum Genet. 2000 Apr;106(4):399-405. Zoll B et al. Evaluation of Cx26/GJB2 in German hearing impaired persons: mutation spectrum and detection of disequilibrium between M34T (c.101T>C) and -493del10. Hum Mutat. 2003 Jan;21(1):98.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000935561.8

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

Description

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 184 of the GJB2 protein (p.Arg184Pro). This variant is present in population databases (rs80338950, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 10874298, 18941476, 19371219, 25708704, 26117665). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17007). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 12176036, 12189493, 12505163, 15241677, 18941476). For these reasons, this variant has been 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 Athena Diagnostics, SCV001476380.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.

#	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: Jun 27, 2026

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Relating variation to medicine