ClinVar Miner

Submissions for variant NM_173354.5(SIK1):c.1463G>T (p.Cys488Phe)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV002510734 SCV002820288 uncertain significance Developmental and epileptic encephalopathy, 30 criteria provided, single submitter clinical testing The missense variant p.C488F in SIK1 (NM_173354.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge.It is observed in 3/30492 (0.0098%) alleles from individuals of South Asian background in the gnomAD dataset There is a large physicochemical difference between cysteine and phenylalanine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.C488F missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1463 in SIK1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV002510734 SCV004475791 uncertain significance Developmental and epileptic encephalopathy, 30 2023-11-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 488 of the SIK1 protein (p.Cys488Phe). This variant is present in population databases (rs769962713, gnomAD 0.01%). 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: 1878643). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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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