ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.550C>T (p.Arg184Trp) (rs998045226)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV001089546 SCV001244786 pathogenic Deafness, autosomal recessive 1A 2017-07-12 criteria provided, single submitter clinical testing The NM_004004.5(GJB2):c.550C>T missense variant identified in exon 2 of GJB2, is predicted to create a major amino acid change from an arginine to a tryptophan at amino acid position 184, NP_003995.2(GJB2):p.(Arg184Trp). The arginine at this position has high conservation (100 vertebrates, UCSC). In silico software predicts this variant to be disease causing. It is situated within the cysteine rich domain of theGJB2 protein. This variant has been observed in a population database at a frequency of 0.00001% (ExAC, GnomAD). This variant has been reported as a pathogenic variant in multiple patients with hearing loss (Deafness variation database, The Connexin-deafness homepage). Based on current information and in association with the NM_004004.5(GJB2):c.101T>C missense variant, this variant has been classified as PATHOGENIC. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive deafness.
Invitae RCV001390263 SCV001591939 pathogenic not provided 2020-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 184 of the GJB2 protein (p.Arg184Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with nonsyndromic deafness (PMID: 14985372, 20650534, 30068397). ClinVar contains an entry for this variant (Variation ID: 560669). 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.Arg184 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10874298, 26117665, 25708704, 18941476, 19371219, 12176036, 15241677, 12505163, 12189493). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678887 SCV000805080 pathogenic Hearing loss 2006-11-10 no assertion criteria provided clinical testing
Hearing and Balance Clinic,First Affliiated Hospital of Kunming Medical University RCV001078465 SCV001190534 pathogenic Deafness, autosomal dominant 3a 2020-03-25 no assertion criteria provided clinical testing Arg184Trp variant in GJB2 has been found in a Chinese family with autosomal recessive inheritance hearing loss, segregated with the disease in the family members. The proband was homozygous of this mutation and the parents carried this variant equally. The proband has bilateral profound hearing loss and the parents have normal hearing .

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