Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000413534 | SCV000491146 | pathogenic | not provided | 2017-05-10 | criteria provided, single submitter | clinical testing | The R297C pathogenic variant has been previously reported multiple individual with SeSAME syndrome who also harbored a second KCNJ10 variant (Scholl et al., 2009, Freudenthal et al., 2011). Functional studies have demostrated that the R297C variant results in impaired protein function (Sala-Rabanal et al., 2010, Tang et al., 2010). The R297C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R297C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with KCNJ10-related disorders (Stenson et al., 2014). |
| Baylor Genetics | RCV000007893 | SCV001520184 | pathogenic | EAST syndrome | 2020-07-31 | criteria provided, single submitter | clinical testing | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Labcorp Genetics |
RCV000007893 | SCV001574872 | pathogenic | EAST syndrome | 2024-10-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 297 of the KCNJ10 protein (p.Arg297Cys). This variant is present in population databases (rs137853071, gnomAD 0.003%). This missense change has been observed in individual(s) with SeSAME syndrome (PMID: 19289823, 21849804). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7467). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNJ10 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ10 function (PMID: 20678478, 20807765, 21088294, 21849804). For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002490337 | SCV002777137 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome; EAST syndrome | 2021-12-30 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000007893 | SCV000028098 | pathogenic | EAST syndrome | 2011-01-01 | no assertion criteria provided | literature only |