Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000187807 | SCV000241405 | uncertain significance | not provided | 2018-07-11 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the KCNJ10 gene. The V84M variant was previously identified as a heterozygous change in an individual with complex partial seizures, severe intellectual disability, and autism; however, this variant was also identified in multiple unaffected family members (Sicca et al., 2011). Although functional studies suggest that V84M results in a gain-of function that leads to neuronal hyperexcitability and altered synaptic function (Sicca et al., 2011; Sicca et al., 2016), no other nearby gain of function variants have been reported in the Human Gene Mutation Database in association with KCNJ10-related disorders (Stenson et al., 2014). The V84M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The V84M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV000807727 | SCV000947796 | uncertain significance | EAST syndrome | 2022-09-13 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 84 of the KCNJ10 protein (p.Val84Met). This variant is present in population databases (rs140646329, gnomAD 0.007%). This missense change has been observed in individual(s) with focal seizures, autism, and developmental delay (PMID: 27677466). ClinVar contains an entry for this variant (Variation ID: 205819). 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 not expected to disrupt KCNJ10 protein function. Experimental studies have shown that this missense change affects KCNJ10 function (PMID: 21458570, 27677466). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Fulgent Genetics, |
RCV002503741 | SCV002817087 | uncertain significance | Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome; EAST syndrome | 2021-10-26 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002514016 | SCV003739959 | uncertain significance | Inborn genetic diseases | 2022-06-07 | criteria provided, single submitter | clinical testing | The c.250G>A (p.V84M) alteration is located in exon 2 (coding exon 1) of the KCNJ10 gene. This alteration results from a G to A substitution at nucleotide position 250, causing the valine (V) at amino acid position 84 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |