ClinVar Miner

Submissions for variant NM_173354.5(SIK1):c.1855C>T (p.Arg619Trp)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002413080 SCV002718016 uncertain significance Inborn genetic diseases 2017-10-09 criteria provided, single submitter clinical testing The p.R619W variant (also known as c.1855C>T), located in coding exon 12 of the SIK1 gene, results from a C to T substitution at nucleotide position 1855. The arginine at codon 619 is replaced by tryptophan, an amino acid with dissimilar properties. This variant did not co-segregate with disease in one individual tested in our laboratory. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV003100891 SCV003517151 uncertain significance Developmental and epileptic encephalopathy, 30 2024-07-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 619 of the SIK1 protein (p.Arg619Trp). 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: 1781393). 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 with a negative predictive value of 95%. 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.

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