Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001266053 | SCV001444225 | uncertain significance | Inborn genetic diseases | 2017-09-28 | criteria provided, single submitter | clinical testing | The p.R355C variant (also known as c.1063C>T), located in coding exon 8 of the SIK1 gene, results from a C to T substitution at nucleotide position 1063. The arginine at codon 355 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of intellectual disability and autism. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV002537683 | SCV003452885 | uncertain significance | Developmental and epileptic encephalopathy, 30 | 2022-06-10 | 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 355 of the SIK1 protein (p.Arg355Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SIK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 985255). 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 SIK1 protein function. 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. |