Submissions for variant NM_004004.6(GJB2):c.368C>A (p.Thr123Asn)

gnomAD frequency: 0.00014  dbSNP: rs111033188

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037845	SCV000061507	likely benign	not specified	2011-06-09	criteria provided, single submitter	clinical testing	Thr123Asn in exon 2 of GJB2: This variant has been previously reported in patien ts with hearing loss as well as in control subjects as a rare polymorphism (Park 2000, Tang 2006, Cryns 2004, Dai 2009, Hwa 2003, Oguchi 2005, Ohtsuka 2003, Shi 2004, Snoeckx 2005). The allele frequencies of this variant are higher in the c ontrol group (~0.9%) than in the patient group (~0.4%), suggesting that this var iant does not have clinical significance.
PreventionGenetics, part of Exact Sciences	RCV000037845	SCV000309915	benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000037845	SCV000342929	likely benign	not specified	2016-06-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000331479	SCV000383006	likely benign	Ichthyosis, hystrix-like, with hearing loss	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000785600	SCV000383007	likely benign	Autosomal dominant nonsyndromic hearing loss 3A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000281969	SCV000383008	likely benign	Autosomal recessive nonsyndromic hearing loss 1A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037845	SCV000698253	benign	not specified	2019-05-06	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.368C>A (p.Thr123Asn) results in a non-conservative amino acid change located in the central part of the cytoplasmic loop (CL) domain (Locke 2009) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. One study indicates potential phosphorylation at this residue, however the functional significance of this post-translational modification is unknown (Locke 2009). The variant allele was found at a frequency of 0.00059 in 255584 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0065 in the gnomAD database, including 1 homozygote. This frequency is lower than the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025) (when considering autosomal recessive inheritance). However, in certain East Asian subpopulations even higher occurrences were reported e.g. in Koreans it was found at a frequency of 0.01 (gnomAD 2.1); that suggests the variant is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has been reported in multiple nonsyndromic sensorineural hearing loss (NSHL) patients (mainly East Asian ethnicity) without strong evidence for causality. The high occurrence in controls and the co-occurrence of other GJB2 disease variants in at least 2 patients argue against a potential dominant inheritance pattern (Dai 2009, Wu 2016). Many studies have reported the variant in patients with comparable frequencies (or lower than) detected in controls (e.g. Dai 2009, Nishio 2017), supporting the benign nature of this variant. A co-occurrence with a pathogenic variant (c.235delC) in trans was reported in a normal-hearing carrier (He 2017); further supporting a benign role for the variant. Though some studies raised the possibility that this variant can contribute to multigenic disorders, postulating that a combination of this variant with heterozygous alterations in other genes may be implicated in deafness (Chow 2017, Wu 2016), they provided no convincing evidence for the causative relationship. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of these laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000785600	SCV000924177	likely benign	Autosomal dominant nonsyndromic hearing loss 3A		criteria provided, single submitter	research
GeneDx	RCV000590041	SCV000969487	likely benign	not provided	2020-10-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15504600, 19043807, 12792423, 15700112, 16380907, 12172394, 22613756, 12560944, 20497192, 31992338, 28900111, 19715472, 30245029, 25262649, 25266519, 10983956, 20607074, 19366456, 14985372, 23638949, 23826813, 17041943, 25388846, 22384008, 22695344, 25493717, 17666888, 20593197, 21162657)
Invitae	RCV000590041	SCV001083006	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477096	SCV002797891	likely benign	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2021-09-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000281969	SCV001453869	likely benign	Autosomal recessive nonsyndromic hearing loss 1A	2020-04-03	no assertion criteria provided	clinical testing