Submissions for variant NM_004004.6(GJB2):c.9G>A (p.Trp3Ter)

dbSNP: rs111033401

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037874	SCV000061536	likely pathogenic	Rare genetic deafness	2008-10-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000666282	SCV000790546	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293597	SCV001482214	pathogenic	Nonsyndromic genetic hearing loss	2021-02-01	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.9G>A (p.Trp3X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249290 control chromosomes (gnomAD). c.9G>A has been reported in the literature in multiple individuals affected with Non-Syndromic Hearing Loss (e.g. Dai_2009, Li_2014, Jung_2017, Yuan_2020). These data indicate that the variant is very likely to be associated with disease. A co-occurrence with two other pathogenic variants in the same sample has been reported following internal testing (GJB2 c.101T>C, p.Met34Thr; GJB2 c.35delG, p.Gly12ValfsX2). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852793	SCV002240126	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp3*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 224 amino acid(s) of the GJB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with non-syndromic deafness (PMID: 21488715, 28383030). ClinVar contains an entry for this variant (Variation ID: 44767). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000666282	SCV002579953	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-05-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496604	SCV002809919	pathogenic	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	2021-12-27	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000666282	SCV005417382	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PM3_VeryStrong
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000666282	SCV000902322	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-02-26	no assertion criteria provided	case-control