ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.365A>T (p.Lys122Ile) (rs111033295)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211721 SCV000061506 likely pathogenic Rare genetic deafness 2012-03-13 criteria provided, single submitter clinical testing The Lys122Ile variant in GJB2 has been reported in 18 probands with hearing loss and was absent from over 400 control samples (Green 1999, Pandya 2003, Tang 200 6, Naghavi 2008). Therefore, this variant is likely to be pathogenic.
Genetic Services Laboratory, University of Chicago RCV000146021 SCV000193173 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000757331 SCV000227322 pathogenic not provided 2012-08-09 criteria provided, single submitter clinical testing
Counsyl RCV000037844 SCV000487642 likely pathogenic Deafness, autosomal recessive 1A 2016-06-24 criteria provided, single submitter clinical testing
Counsyl RCV000412394 SCV000487643 likely pathogenic Deafness, autosomal dominant 3a 2016-06-24 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000037844 SCV000599748 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000037844 SCV000698252 pathogenic Deafness, autosomal recessive 1A 2016-06-01 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.365A>T (p.Lys122Ile) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 6/121646 control chromosomes at a frequency of 0.0000493, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). This variant has been identified in compound heterozygous state in patients with non-syndromic hearing loss, and is considered pathogenic in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757331 SCV000885515 likely pathogenic not provided 2017-10-20 criteria provided, single submitter clinical testing The p.Lys122Ile variant (rs111033295) has been reported in the medical literature in multiple individuals with hearing loss (de la Luz Arenas-Sordo 2012, Green 1999, Naghavi 2008, Pandya 2007, Prasad 2000, and Tang 2006), and it has been previously identified by our laboratory in several patients who were referred for hearing loss. The p.Lys122Ile variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.039% in the Latino population (identified in 13 out of 33,572 chromosomes), which is consistent with a recessive carrier frequency. Furthermore, the p.Lys122Ile is classified as pathogenic/likely pathogenic in ClinVar (Variant ID: 44742). The lysine at codon 122 is highly conserved considering 10 species up to frog (Alamut software v2.10.0), and computational analyses suggest that this variant does affect the structure/function of the GJB2 protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). Therefore, based on the available evidence, the p.Lys122Ile variant is classified as likely pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000412394 SCV000996215 pathogenic Deafness, autosomal dominant 3a 2018-11-25 criteria provided, single submitter clinical testing This variant was reported as pathogenic in the compound heterozygous state in patients with Deafness, autosomal recessive 1 (PMID: 25388846 and 10376574). This variant has also been previously reported as a heterozygous change in patients with hearing loss of an unspecified inheritance pattern (PMID: 12865758, 16222667, 17041943, 18776652). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0053% (13/245106) and thus is presumed to be rare. The c.365A>T (p.Lys122Ile) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.365A>T (p.Lys122Ile) variant is classified as pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678882 SCV000805075 pathogenic Hearing loss 2013-12-19 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.