ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.59T>C (p.Ile20Thr) (rs1057517519)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410601 SCV000487696 likely pathogenic Deafness, autosomal recessive 1A 2016-08-09 criteria provided, single submitter clinical testing
Counsyl RCV000411693 SCV000487697 likely pathogenic Deafness, autosomal dominant 3a 2016-08-09 criteria provided, single submitter clinical testing
Invitae RCV001234615 SCV001407270 pathogenic not provided 2020-09-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 20 of the GJB2 protein (p.Ile20Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with deafness (PMID: 11313763, 16380907, 12189487). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 371766). This variant has been reported to affect GJB2 protein function (PMID: 16217030). For these reasons, this variant has been classified as Pathogenic.
INGEBI, INGEBI / CONICET RCV001257156 SCV001433673 pathogenic Nonsyndromic hearing loss and deafness 2020-08-31 criteria provided, single submitter clinical testing Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.59T>C, p.Ile20Thr variant in GJB2 gene is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. Computational evidence predicted a pathogenic effect of the mutation to the protein applying to PP3 rule (REVELscore: 0.931). This variant has been identified in trans with pathogenic variants and in homozygous state in at least 4 patients with hearing impairment meeting PM3_VeryStrong (PMID: 11313763, 12189487, 16380907, 25401782, Laboratory of Physiology and Genetics of Hearing, INGEBI internal data). Besides, homozygous p.Ile20Thr change segregated in two brothers with hearing loss applying to PP1_Supporting rule (Laboratory of Physiology and Genetics of Hearing, INGEBI internal data). Functional studies in HEK293 cells demonstrated that p.Ile20Thr mutant exhibited a reduction of ionic permeability by two-electrode patch clamp recording experiment (PMID: 16217030) meeting PS3_Moderate. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2, PP3, PM3_VeryStrong, PP1_Supporting, PS3_Moderate.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678863 SCV000805056 pathogenic Hearing loss 2008-09-11 no assertion criteria provided clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV001374656 SCV001571587 pathogenic nonsyndromic sensorineural hearing loss 2021-02-19 no assertion criteria provided clinical testing

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