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

Total submissions: 19

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 Medical Center	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	2016-12-19	criteria provided, single submitter	clinical testing
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.
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