ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.60T>G (p.Ile20Met)

gnomAD frequency: 0.00001  dbSNP: rs749693224
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000505534 SCV000599726 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2017-05-09 criteria provided, single submitter clinical testing
Counsyl RCV000505534 SCV000797602 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2018-01-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001112642 SCV001270325 uncertain significance Autosomal dominant nonsyndromic hearing loss 3A 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services,Illumina RCV001112643 SCV001270326 uncertain significance Ichthyosis, hystrix-like, with hearing loss 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services,Illumina RCV000505534 SCV001270327 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV001857232 SCV002261512 likely pathogenic not provided 2021-10-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 20 of the GJB2 protein (p.Ile20Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs749693224, ExAC 0.001%). This variant has been observed in individual(s) with deafness (PMID: 12172394, 12910486, 17666888). ClinVar contains an entry for this variant (Variation ID: 438615). 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 variant disrupts the p.Ile20 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11313763, 12189487, 16217030, 16380907). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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