ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.326G>A (p.Gly109Glu)

gnomAD frequency: 0.00005  dbSNP: rs374572413
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV001375241 SCV001572039 uncertain significance Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PM2_Moderate, PM5_Moderate, PP3_Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271648 SCV002556271 uncertain significance not specified 2022-06-30 criteria provided, single submitter clinical testing Variant summary: GJB2 c.326G>A (p.Gly109Glu) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) in the last exon of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.326G>A has been reported in the literature in at-least one individual from the Iranian province of Semnan within a cohort of deaf probands who has been subsequently cited by others (example, Bazazzadegan_2012, Koohiyan_2019). These reports do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002499771 SCV002814638 uncertain significance 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 2022-03-20 criteria provided, single submitter clinical testing
GeneDx RCV003327514 SCV004034380 uncertain significance not provided 2023-09-01 criteria provided, single submitter clinical testing Observed in a patient with hearing loss in published literature (Bazazzadegan et al., 2012); however, additional patient level information was not provided; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25388846, 31569309, 25087612, 22695344, 36048236)

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