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rs80338950

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_004004.6(GJB2):c.551G>C(p.Arg184Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R184Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

15
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 7.86
Variant links:
Genes affected
GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004004.6
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-20189031-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
Variant 13-20189031-C-G is Pathogenic according to our data. Variant chr13-20189031-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 17007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189031-C-G is described in Lovd as [Likely_pathogenic]. Variant chr13-20189031-C-G is described in Lovd as [Pathogenic]. Variant chr13-20189031-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GJB2NM_004004.6 linkuse as main transcriptc.551G>C p.Arg184Pro missense_variant 2/2 ENST00000382848.5
GJB2XM_011535049.3 linkuse as main transcriptc.551G>C p.Arg184Pro missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GJB2ENST00000382848.5 linkuse as main transcriptc.551G>C p.Arg184Pro missense_variant 2/21 NM_004004.6 P1
GJB2ENST00000382844.2 linkuse as main transcriptc.551G>C p.Arg184Pro missense_variant 1/1 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152120
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251296
Hom.:
0
AF XY:
0.0000663
AC XY:
9
AN XY:
135832
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461770
Hom.:
0
Cov.:
32
AF XY:
0.0000330
AC XY:
24
AN XY:
727170
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152120
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000526
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:6Other:1
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaOct 18, 2018Across 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; Thönnissen 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. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 23, 2016Variant 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. -
Pathogenic, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaMay 09, 2017- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2004- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Aug 12, 2020- -
Pathogenic, no assertion criteria providedclinical testingCounsylSep 09, 2016- -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 16, 2024This 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 nonsyndromic 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 25, 2020The 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. -
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncJul 23, 2020The 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. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 07, 2022Published 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) -
Hearing loss Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalJun 01, 2015- -
Nonsyndromic genetic hearing loss Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingINGEBI, INGEBI / CONICETAug 31, 2020Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filter allele frequency of c.551G>C, p.Arg184Pro variant in GJB2 gene is 0,0038% (4/35426 Latino alleles with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2 criteria. This variant was identified at least in five individuals in trans with several known pathogenic variants (PM3_VeryStrong; PMID: 24158611, 10874298, 10982180, 11551103, 12176179, 16380907, 16380907, 17485979). Computational evidence predicted a damage impact of the mutation to the protein meeting PP3 rule (REVELscore: 0,983) Functional studies demonstrated that: mutant protein is neither trafficked to membrane nor able to oligomerize efficiently and unable to form functional GJCh in HeLa cells (PMID: 12176036, 1218943). Moreover, p.Arg184Pro mutant did not induce the formation of homotypic junctional channels, since the levels of conductance measured never exceeded background values in Xenopus laevis oocytes (PMID: 12505163), PS3_Moderate Therefore, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PM3_VeryStrong, PP3 and PS3_Moderate). -
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 26, 2019This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3,PP5. -
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 30, 2014The p.Arg184Pro variant in GJB2 has been identified in the homozygous or compoun d heterozygous state in more than 50 individuals with hearing loss, and in vitro functional studies provide some evidence that this variant may impact protein f unction (Thonnissen 2002, Bruzzone 2003, Mani 2009). This variant has been iden tified in 1/11568 of Latino chromosomes, 1/16592 of South Asian chromosomes, and 3/67458 of European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs80338950). Although this variant has been se en in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, the p.Arg184Pro variant meets our cr iteria to be classified as pathogenic for autosomal recessive hearing loss based upon strong association with the disease, low frequency in the general populati on, and supportive functional evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.58
Cadd
Pathogenic
28
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D;D;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.1
H;H;H
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-6.1
D;D;.
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;.
Sift4G
Pathogenic
0.0
D;D;.
Polyphen
1.0
D;D;D
Vest4
0.99
MVP
0.97
MPC
0.32
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.99
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338950; hg19: chr13-20763170; API