ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.269T>C (p.Leu90Pro) (rs80338945)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 Deafness, autosomal dominant 3a 2016-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000080369 SCV000490535 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing The L90P variant in the GJB2 gene has been reported previously as homozygous or compound heterozygous pathogenic variant in individuals with autosomal recessive non-syndromic hearing loss (DFNB1) and seems especially common in the Italian population (for example see: Denoyelle et al., 1999; D'Andrea et al., 2002; Beck et al., 2014; Tekin et al., 2016). The L90P variant is observed in 151/126606 (0.12%) alleles from individuals of European (non-Finnish) background, in the ExAC dataset (Lek et al., 2016). L90P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in the second transmembrane domain of connexin 26 at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same (L90R, L90V) have been reported in the Human Gene Mutation Database in association with DFNB1 (Stenson et al., 2014). In addition, functional in vitro studies have shown that the L90P variant impedes formation of functional gap junction channels and hemichannels but does not interfere with co-expressed wildtype protein, consistent with its autosomal recessive inheritance (D'Andrea et al., 2002; Thonnissen et al., 2002; Palmada et al., 2006). Therefore, we interpret L90P as a pathogenic variant.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415167 SCV000492908 pathogenic Congenital omphalocele; Hearing impairment; Horseshoe kidney; Short palpebral fissure 2013-12-18 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000018541 SCV000538033 pathogenic Deafness, autosomal recessive 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.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000018541 SCV000599742 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507991 SCV000603829 pathogenic not specified 2018-08-08 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, Mikstiene 2016, Snoeckx 2005). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 17016), and is found in the non-Finnish European population with an overall allele frequency of 0.12% (151/126606 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.269T>G, p.Leu89Arg; c.268C>G, p.Leu90Val) have been reported in individuals with mild hearing loss (Lipan 2011, Lim 2003). Functional analyses of the variant protein shows significant loss of junctional conductance (Bruzzone 2003, D'Andrea 2002, Palmada 2006, Thonnissen 2002). The leucine at codon 90 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Bruzzone 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. D'Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 Aug 23;296(3):685-91. Denoyelle 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 Apr 17;353(9161):1298-303. 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 Aug;111(2):145-53. Lipan M et al. Clinical comparison of hearing-impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations. Laryngoscope. 2011 Apr;121(4):811-4. Lim et al. Genotypic and phenotypic correlations of DFNB1-related hearing impairment in the Midwestern United States. Arch Otolaryngol Head Neck Surg. 2003; 129(8):836-40. 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 Feb 19;17:45. Palmada M et al. Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. Neurobiol Dis. 2006 Apr;22(1):112-8. Snoeckx, RJ et al.: GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study. Am J Hum Genet 2005; 77:945-957. 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.
Fulgent Genetics,Fulgent Genetics RCV000515450 SCV000611269 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Keratoderma palmoplantar deafness; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 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 Deafness, autosomal recessive 1A 2019-01-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000018541 SCV000919425 pathogenic Deafness, autosomal recessive 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 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 90 of the GJB2 protein (p.Leu90Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs80338945, ExAC 0.2%). This variant has been observed to segregate with autosomal recessive deafness in families (PMID: 12189487) and has been reported with another GJB2 variant in many individuals affected with deafness (PMID: 10218527, 12189487, 15365987, 12497637, 12172392). ClinVar contains an entry for this variant (Variation ID: 17016). Experimental studies have shown that this missense change results in a defective GJB2 protein (PMID: 12189493, 16300957). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004391 SCV001163363 pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b criteria provided, single submitter clinical testing
OMIM RCV000018541 SCV000038823 pathogenic Deafness, autosomal recessive 1A 2001-03-01 no assertion criteria provided literature only
GeneReviews RCV000018541 SCV000041043 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000018541 SCV000487391 pathogenic Deafness, autosomal recessive 1A 2016-03-08 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678875 SCV000805068 pathogenic Hearing loss 2016-11-02 no assertion criteria provided clinical testing

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