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

gnomAD frequency: 0.00001  dbSNP: rs111033295

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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
Eurofins Ntd Llc (ga)	RCV000757331	SCV000227322	pathogenic	not provided	2012-08-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000037844	SCV000487642	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-06-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000412394	SCV000487643	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 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	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037844	SCV000698252	pathogenic	Autosomal recessive nonsyndromic hearing loss 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	Autosomal dominant nonsyndromic hearing loss 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	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.
GeneDx	RCV000757331	SCV001811451	likely pathogenic	not provided	2024-09-04	criteria provided, single submitter	clinical testing	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: 26275501, 25447126, 12865758, 10751669, 10376574, 25388846, 16125251, 22925408, 32003480, 17041943, 15365987, 11102979, 19235794, 17666888, 19081147, 18368581, 16222667, 12408072, 18776652, 10980526, 12067629, 26444186, 12457340, 30708180, 10704187, 31160754, 38855775, 34645491, 36048236)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000757331	SCV002228261	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 122 of the GJB2 protein (p.Lys122Ile). This variant is present in population databases (rs111033295, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of autosomal recessive nonsyndromic deafness (PMID: 10376574, 22925408, 31160754; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 44742). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004018850	SCV004876988	pathogenic	Inborn genetic diseases	2022-11-30	criteria provided, single submitter	clinical testing	The c.365A>T (p.K122I) alteration is located in exon 2 (coding exon 1) of the GJB2 gene. This alteration results from an A to T substitution at nucleotide position 365, causing the lysine (K) at amino acid position 122 to be replaced by an isoleucine (I)._x000D_ _x000D_ Based on the available evidence, the GJB2 c.365A>T (p.K122I) alteration is classified as pathogenic for autosomal recessive GJB2-related nonsyndromic hearing loss; however, its clinical significance for autosomal dominant GJB2-related nonsyndromic hearing loss and GJB2-related syndromic hearing loss with ectodermal involvement is unclear. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (15/250324) total alleles studied. The highest observed frequency was 0.043% (15/34582) of Latino alleles. This variant has been identified with a second GJB2 variant in multiple individuals with hearing loss (Green, 1999; Putcha, 2007; Lee, 2009; de la Luz Arenas-Sordo, 2012; Shen, 2019). This variant has also been reported in the absence of a second GJB2 alteration in multiple heterozygous individuals with hearing loss (Azaiez, 2004; Cheng, 2005; Tang, 2006; Naghavi, 2008; Tayoun, 2016). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration 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