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

dbSNP: rs1057517519

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410601	SCV000487696	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-08-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000411693	SCV000487697	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-08-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001234615	SCV001407270	pathogenic	not provided	2023-07-16	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects GJB2 function (PMID: 16217030). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 20 of the GJB2 protein (p.Ile20Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 11313763, 12189487, 16380907). 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: 371766).
INGEBI, INGEBI / CONICET	RCV001257156	SCV001433673	pathogenic	Nonsyndromic genetic hearing loss	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.
GeneDx	RCV001234615	SCV005325973	pathogenic	not provided	2023-11-28	criteria provided, single submitter	clinical testing	Observed multiple times with a pathogenic GJB2 variant in individuals with nonsyndromic hearing loss, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 31370293, 11313763, 16380907); Published functional studies demonstrate a damaging effect: exhibited a reduction of ionic permeability (PMID: 16217030); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33096615, 24256046, 25388846, 11313763, 33105617, 16380907, 25401782, 12189487, 31370293, 16217030)
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
Natera, Inc.	RCV000410601	SCV002086068	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-03-22	no assertion criteria provided	clinical testing