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

Total submissions: 10

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