ClinVar Miner

Submissions for variant NM_001330260.2(SCN8A):c.2287A>G (p.Ile763Val) (rs794727128)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000174766 SCV000226132 likely pathogenic not provided 2018-03-02 criteria provided, single submitter clinical testing
GeneDx RCV000174766 SCV000242897 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing The I763V variant in the SCN8A gene has been reported previously reported as a de novo finding in two brothers with seizures and developmental delay consistent with germline mosaicism in a parent (Butler et al., 2017). The I763V variant is not observed in large population cohorts (Lek et al., 2016). The I763V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014). We interpret I763V as a pathogenic variant.
Invitae RCV001044209 SCV001207993 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 763 of the SCN8A protein (p.Ile763Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 27875746). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 194402). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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.
GenomeConnect, ClinGen RCV000509479 SCV000606944 not provided SCN8A-related disorder no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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