ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5582G>A (p.Arg1861Gln) (rs796053042)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481884 SCV000570875 likely pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing The R1861Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It 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 R1861Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, this substitution occurs at a conserved position in the C-terminal cytoplasmic region of the Nav1.1 alpha subunit (Escayg et al., 2010). A different missense variant in the same codon (R1861W), as well as multiple missense variants in nearby residues have been reported in association with SCN1A-related disorders (Stenson et al., 2014; Wang et al., 2012), supporting the functional importance of this region of the protein. Therefore, the R1861Q variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001043102 SCV001206817 uncertain significance Early infantile epileptic encephalopathy 2019-06-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1861 of the SCN1A protein (p.Arg1861Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in one or more individuals who were not affected with SCN1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 421612). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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