ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)

gnomAD frequency: 0.00066  dbSNP: rs80338945
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 39
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000211772 SCV000061493 pathogenic Rare genetic deafness 2017-08-10 criteria provided, single submitter clinical testing The p.Leu90Pro variant in GJB2 is a common, well-known pathogenic variant for au tosomal recessive nonsyndromic hearing loss (Cryns 2004). The p.Leu90Pro variant has been identified in 0.12% (151/126606) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs8033894 5). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency for hearing l oss. In summary, this variant meets criteria to be classified as pathogenic for non-syndromic hearing loss in an autosomal recessive manner. ACMG/AMP Criteria a pplied: PM3_VeryStrong; PS3; PP1; PP3.
Genetic Services Laboratory,University of Chicago RCV000146013 SCV000193164 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000080369 SCV000227315 pathogenic not provided 2014-11-10 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000146013 SCV000264603 pathogenic Hearing impairment 2015-12-01 criteria provided, single submitter research
Counsyl RCV000409625 SCV000487392 pathogenic Autosomal dominant nonsyndromic hearing loss 3A 2016-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000080369 SCV000490535 pathogenic not provided 2020-01-20 criteria provided, single submitter clinical testing Reported in the published literature as homozygous or compound heterozygous with another pathogenic variant in individuals with mild to profound autosomal recessive non-syndromic hearing loss (DFNB1) (Denoyelle et al., 1999; Beck et al., 2015; Tekin et al., 2016; Loeffler et al., 2001); This variant seems common among the Italian and Lithuanian populations (D'Andrea et al., 2002; Mikstiene et al., 2016); In vitro electrophysiological and functional studies demonstrate that L90P impedes formation of functional gap junction channels and hemichannels but does not interfere with function of co-expressed wildtype protein, consistent with its autosomal recessive inheritance (D'Andrea et al., 2002; Thonnissen et al., 2002; Palmada et al., 2006); 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: 27177978, 26850479, 27481527, 30609409, 29554876, 31980526, 22975760, 25087612, 10218527, 12189493, 12176036, 12505163, 16300957, 27224056, 26896187, 25214170, 11313763, 12189487, 27153395, 14738110, 25388846, 29293505, 30094485, 30344259, 31160754, 33096615, 31589614, 32860223)
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000018541 SCV000492908 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2013-12-18 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000018541 SCV000538033 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2016-02-25 criteria provided, single submitter clinical testing The c.269T>C (p.Leu90Pro) missense variant in the GJB2 gene is a common variant reported in individuals affected with autosomal recessive nonsyndromic hearing loss and deafness (Löffler et al., 2001). This variant has been observed in trans with the well-characterized GJB2c.35delG variant (Denoyelle et al., 1999, Löffler et al., 2001). Multiple studies have shown this variant impairs proper assembly and function of the gap junction channel (Thönnissen et al., 2002; D'Andrea et al., 2002; Bruzzone et al., 2003; Palmada et al., 2006). This c.269T>C has been reported at low frequency or absent in three control population databases (Exome Sequencing Project [ESP] = 0.058%, 1000 Genomes = NA, and ExAC = 0.151%). Multiple lines of computational evidence predict a deleterious effect (GERP = 5.33; CADD = 23.5; PolyPhen = 1; SIFT = 0), and multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.269T>C (p.Leu90Pro) as a recessive pathogenic variant for Nonsyndromic hearing loss and deafness.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000018541 SCV000599742 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000080369 SCV000603829 pathogenic not provided 2021-07-12 criteria provided, single submitter clinical testing The GJB2 c.269T>C; p.Leu90Pro variant (rs80338945) is reported in the literature in multiple individuals and families affected with mild to moderate hearing loss (Denoyelle 1999, Janecke 2002, Likar 2018, Mikstiene 2016, Snoeckx 2005). This variant is reported in ClinVar (Variation ID: 17016), and is found predominantly in the non-Finnish European population with an allele frequency of 0.12% (153/129066 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.269T>G; p.Leu90Arg and c.268C>G; p.Leu90Val) have been reported in individuals with mild hearing loss (Lim 2003, Lipan 2011). Functional analyses of the p.Leu90Pro variant protein shows significant loss of junctional conductance (Bruzzone 2003, D'Andrea 2002, Palmada 2006, Thonnissen 2002). Based on available information, this variant is considered to be pathogenic. REFERENCES Bruzzone R et al. Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett. 2003 533:79-88. PMID: 12505163. D'Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 296:685-691. PMID: 12176036. Denoyelle F et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet. 1999 353:1298-1303. PMID: 10218527. Janecke AR et al. Progressive hearing loss, and recurrent sudden sensorineural hearing loss associated with GJB2 mutations--phenotypic spectrum and frequencies of GJB2 mutations in Austria. Hum Genet. 2002 111:145-153. PMID: 12189487. Likar T et al. Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss. PLoS One. 2018 13:e0188578. PMID: 29293505. Lim LH et al. Genotypic and phenotypic correlations of DFNB1-related hearing impairment in the Midwestern United States. Arch Otolaryngol Head Neck Surg. 2003 129:836-840. PMID: 12925341. Lipan M et al. Clinical comparison of hearing-impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations. Laryngoscope. 2011 121:811-814. PMID: 21287563. Mikstiene V et al. The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population. BMC Genet. 2016 17:45. PMID: 26896187. Palmada M et al. Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. Neurobiol Dis. 2006 22:112-118. PMID: 16300957. Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 77:945-957. PMID: 16380907. 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 111:190-197. PMID: 12189493.
Fulgent Genetics,Fulgent Genetics RCV000515450 SCV000611269 pathogenic Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000080369 SCV000613509 pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network,NIH RCV000018541 SCV000863417 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2019-01-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000018541 SCV000919425 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2017-09-01 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.269T>C (p.Leu90Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, and this mutation affects a highly conserved residue of the encoded gap junction protein and has been shown to be coupling deficient by in vitro functional assays (Thonnissen_2001). The observed allele frequency in controls, including the large and diverse ExAC cohort, is 108/123096 (1/1140), which is lower than the maximal expected allele frequency for an ARNSHL-causing GJB2 variant (1/40). This variant has been reported in several NSHL patients in homozygous as well as compound heterozygous state with other pathogenic variants, including evidence of cosegregation with disease in multiple families (Rabionet_2000, Marlin_2001, Tang_2006, Salvago_2014). In addition, several diagnostic laboratories/reputable databases classify the variant as pathogenic. Taking all evidence together, this variant has been classified as pathogenic.
Invitae RCV000080369 SCV000944408 pathogenic not provided 2021-12-17 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 90 of the GJB2 protein (p.Leu90Pro). This variant is present in population databases (rs80338945, gnomAD 0.1%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 10218527, 12172392, 12189487, 12497637, 15365987). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17016). 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. Experimental studies have shown that this missense change affects GJB2 function (PMID: 12189493, 16300957). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004391 SCV001163363 pathogenic Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000018541 SCV001193908 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2019-12-07 criteria provided, single submitter clinical testing NM_004004.5(GJB2):c.269T>C(L90P) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 12505163, 10830906, 12189493, 12189487, 15967879, and 21094084. Classification of NM_004004.5(GJB2):c.269T>C(L90P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen RCV000080369 SCV001245651 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001109788 SCV001267158 benign Ichthyosis, hystrix-like, with hearing loss 2017-04-27 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services,Illumina RCV000409625 SCV001271710 likely benign Autosomal dominant nonsyndromic hearing loss 3A 2017-04-27 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000409625 SCV001368641 pathogenic Autosomal dominant nonsyndromic hearing loss 3A 2019-01-10 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP2,PP3.
INGEBI, INGEBI / CONICET RCV001257157 SCV001433675 pathogenic Nonsyndromic genetic hearing loss 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.269T>C, p.Leu90Pro variant in GJB2 gene is 0.1% (153/129066 European non-Finnish 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 BS1_Supporting rule. Computational analysis of p.Leu90Pro change predicted a damage impact to the protein (REVELscore:0.981; PP3). This variant has been identified in at least 15 hearing loss individuals in trans with c.35delG variant and in trans with several known pathogenic variants meeting PM3_VerySrong (PMID: 10218527, 10830906, 10982180, 11313763, 11493200, 12176179, 14985372, 15967879, 163800907, 19173109, 24158611). Functional studies in HeLa cells showed that p.Leu90Pro mutant displayed neither very low incidence of dye transfer (LY and DAPI), not tracer (neurobitin) diffusion (PMID: 12176036, 12189493). In addition to this, electrophysiological recordings in Xenopus Laevis oocytes demonstrated that there was not junctional conductance levels detected when p.Leu90Pro mutant was injected (PMID: 12505163). Besides, partial dominant effect on hCX30 was determined but not on CX26; PS3_Moderate. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: BS1_Supporting, PP3, PM3_VeryStrong, PS3_Moderate.
Institute of Human Genetics, University of Leipzig Medical Center RCV001109788 SCV001440320 pathogenic Ichthyosis, hystrix-like, with hearing loss 2019-01-01 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000080369 SCV001449022 pathogenic not provided 2016-09-21 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000080369 SCV001449716 pathogenic not provided 2018-03-14 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000080369 SCV001480166 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000018541 SCV001523117 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2019-04-19 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV000146013 SCV001571775 pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM2_Moderate, PM3_Supporting, PM5_Moderate, PP3_Supporting
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001762051 SCV002009982 pathogenic Mutilating keratoderma 2021-11-03 criteria provided, single submitter clinical testing
DASA RCV001775068 SCV002011888 pathogenic Deafness 2021-09-02 criteria provided, single submitter clinical testing The missense variant c.269T>C;p.(Leu90Pro) in the GJB2 gene is classified as pathogenic related with DFNB1 nonsyndromic hearing (ClinVar ID: 17016; OMIM: 121011.0016; PMID: 11313763; 26896187; 20301449; 25214170; 24793888; 12176036; 16300957; 24158611; 22281373; 22037723; 33333757; 29293505; 29311818; 25189242) – PS4. This variant is present at very low allele frequencies population databases (rs80338945 - gnomAD; ABraOM) - PM2_ supporting. The p.Leu90Pro was detected in trans with a pathogenic variant (PMID: 25214170; 24793888; 26896187; 24158611; 22281373; 22037723; 29293505; 25189242) - PM3_very strong; and the predictions coincide with pathogenicity – PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Institute of Human Genetics, University Hospital Muenster RCV002227041 SCV002506418 pathogenic See cases 2018-07-16 criteria provided, single submitter clinical testing ACMG categories: PS3,PM2,PM3,PP3,PP5
OMIM RCV000018541 SCV000038823 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2001-03-01 no assertion criteria provided literature only
GeneReviews RCV000018541 SCV000041043 pathologic Autosomal recessive nonsyndromic hearing loss 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678875 SCV000805068 pathogenic Hearing loss 2016-11-02 no assertion criteria provided clinical testing
Natera, Inc. RCV000018541 SCV001453341 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000080369 SCV001739866 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000080369 SCV001973113 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000080369 SCV001979732 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000080369 SCV002024254 pathogenic not provided 2020-12-11 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.