ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5563C>T (p.Pro1855Ser) (rs794727415)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000484175 SCV000228323 uncertain significance not provided 2014-06-06 criteria provided, single submitter clinical testing
GeneDx RCV000484175 SCV000569513 likely pathogenic not provided 2017-02-02 criteria provided, single submitter clinical testing A novel P1855S variant that is likely pathogenic has been identified in the SCN1A gene. The P1855S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different missense variant at the same position (P1855L) was reported previously as a de novo variant in an individual with Dravet syndrome (Zuberi et al., 2011). The P1855S variant 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 P1855S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position predicted to be within the C-terminal cytoplasmic domain. Missense variants in nearby residues (M1852T, M1856T, V1857L) have been reported in association with SCN1A-related disorders (Stenson et al., 2014; SCN1A Variant Database), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001057823 SCV001222338 uncertain significance Early infantile epileptic encephalopathy 2019-04-04 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1855 of the SCN1A protein (p.Pro1855Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual referred for genetic testing for epilepsy (PMID: 29056246). ClinVar contains an entry for this variant (Variation ID: 195945). 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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