ClinVar Miner

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

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Total submissions: 11
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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
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,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 RCV000999926 SCV000885515 likely pathogenic not specified 2019-02-02 criteria provided, single submitter clinical testing The GJB2 c.365A>T; p.Lys122Ile (rs111033295) is reported in the literature in multiple individuals with hearing loss (de la Luz Arenas-Sordo 2012, Green 1999, Lee 2009, Naghavi 2008, Pandya 2007, Prasad 2000, Putcha 2007, Tang 2006), and it has been previously identified by our laboratory in several patients who were referred for hearing loss. Several affected individuals were found to carry an additional pathogenic variant (de la Luz Arenas-Sordo 2012, Lee 2009, Putcha 2007). The p.Lys122Ile variant is classified as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variant ID: 44742) and it is found in the Latino population with an overall allele frequency of 0.04% (15/34582 alleles) in the Genome Aggregation Database. The lysine at codon 122 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on the available information, the p.Lys122Ile variant is classified as likely pathogenic. References: de la Luz Arenas-Sordo et al. Unique spectrum of GJB2 mutations in Mexico. Int J Pediatr Otorhinolaryngol. 2012 Nov;76(11):1678-80. doi: 10.1016/j.ijporl.2012.08.005. Epub 2012 Aug 24. Green et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Lee et al. Audiologic and temporal bone imaging findings in patients with sensorineural hearing loss and GJB2 mutations. Laryngoscope. 2009 Mar;119(3):554-8. Naghavi et al. GJB2 mutations in Baluchi population. J Genet. 2008 Aug;87(2):195-7. Pandya et al. Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands. Genet Med. 2003 Jul-Aug;5(4):295-303. Prasad et al. Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). Hum Mutat. 2000 Dec;16(6):502-8. Putcha et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Tang et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006 Nov 15;140(22):2401-15.
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.
Athena Diagnostics Inc RCV000757331 SCV001143667 pathogenic not provided 2018-08-29 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678882 SCV000805075 pathogenic Hearing loss 2013-12-19 no assertion criteria provided clinical testing

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