ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.2686G>A (p.Val896Ile) (rs745378416)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000986896 SCV001136046 uncertain significance Severe myoclonic epilepsy in infancy 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001204733 SCV001375952 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2019-08-25 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 896 of the SCN1A protein (p.Val896Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs745378416, ExAC no frequency). This variant has been observed in individuals affected with intractable epilepsy, however in one of these individuals a different pathogenic variant in SCN1A was also identified (PMID: 22780858, 23195492). 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. This variant disrupts the p.Val896 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18930999, 23195492). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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