ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.587T>C (p.Ile196Thr)

gnomAD frequency: 0.00004  dbSNP: rs765172751
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000516988 SCV000613519 uncertain significance not specified 2016-10-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000516988 SCV001361879 uncertain significance not specified 2019-11-22 criteria provided, single submitter clinical testing Variant summary: GJB2 c.587T>C (p.Ile196Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251346 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.587T>C has been reported in the literature in one individual affected with Non-Syndromic Hearing Loss (Felix_2019) and a newborn screening (Qingjia_2015). These reports do not provide an unequivocal conclusion 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. A ClinVar submission (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc. RCV001810456 SCV002060097 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2021-11-01 criteria provided, single submitter clinical testing NM_004004.5(GJB2):c.587T>C(I196T) is a missense variant classified as a variant of uncertain significance in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. I196T has been observed in cases with relevant disease (PMID: 31992338, 29773520). Functional assessments of this variant are not available in the literature. I196T has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, there is insufficient evidence to classify NM_004004.5(GJB2):c.587T>C(I196T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics RCV002476042 SCV002784747 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 2021-10-27 criteria provided, single submitter clinical testing
Invitae RCV002525035 SCV003456180 uncertain significance not provided 2022-10-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 196 of the GJB2 protein (p.Ile196Thr). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 29773520, 31992338; 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: 447447). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc. RCV001810456 SCV002094993 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2020-11-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.