ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.551G>C (p.Arg184Pro) (rs80338950)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211781 SCV000061525 pathogenic Rare genetic deafness 2014-10-30 criteria provided, single submitter clinical testing The 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 ://; 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000018531 SCV000599760 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000018531 SCV000698267 pathogenic Deafness, autosomal recessive 1A 2016-03-23 criteria provided, single submitter clinical testing 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.
GeneDx RCV000657913 SCV000779679 pathogenic not provided 2018-05-07 criteria provided, single submitter clinical testing The R184P variant has been published as a pathogenic variant in association with sensorineural hearing loss (Lameiras et al., 2015; Mani et al., 2009). In vitro functional studies demonstrated that the presence of the R184P variant resulted in the failure of intracellular coupling and gap junction channel formation (Thönnissen et al., 2002; Bruzzone et al., 2003). The R184P variant is observed in 3/34416 (0.009%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The R184P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Other pathogenic missense variants in this residue (R184Q/W/G) have been reported in the Human Gene Mutation Database in association with hearing loss (Stenson et al., 2014). In summary, based on the currently available information, this variant is pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999734 SCV000885514 pathogenic none provided 2019-09-24 criteria provided, single submitter clinical testing 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.
Fulgent Genetics,Fulgent Genetics RCV000763321 SCV000893998 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000018531 SCV000914611 pathogenic Deafness, autosomal recessive 1A 2018-10-18 criteria provided, single submitter clinical testing 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; 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.
Invitae RCV000657913 SCV000935561 pathogenic not provided 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 184 of the GJB2 protein (p.Arg184Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs80338950, ExAC 0.009%). This variant has been observed in many individuals with autosomal recessive nonsyndromic hearing loss and to segregate with hearing loss in a family (PMID: 10874298, 26117665, 25708704, 18941476, 19371219). ClinVar contains an entry for this variant (Variation ID: 17007). This variant has been reported to affect GJB2 protein function (PMID: 12176036, 15241677, 18941476, 12505163, 12189493). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV001112461 SCV001270121 likely benign Hystrix-like ichthyosis with deafness 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001112462 SCV001270122 uncertain significance Deafness, autosomal dominant 3a 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001112462 SCV001366460 pathogenic Deafness, autosomal dominant 3a 2019-01-26 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3,PP5.
INGEBI, INGEBI / CONICET RCV001257160 SCV001433678 pathogenic Nonsyndromic hearing loss and deafness 2020-08-31 criteria provided, single submitter clinical testing Based 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 (; calculated by using inverse allele frequency at, 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).
Athena Diagnostics Inc RCV000657913 SCV001476380 pathogenic not provided 2020-07-23 criteria provided, single submitter clinical testing 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.
OMIM RCV000018531 SCV000038813 pathogenic Deafness, autosomal recessive 1A 2004-02-01 no assertion criteria provided literature only
GeneReviews RCV000018531 SCV000041050 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000018531 SCV000220825 pathogenic Deafness, autosomal recessive 1A 2016-09-09 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678888 SCV000805081 pathogenic Hearing loss 2015-06-01 no assertion criteria provided clinical testing

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