ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.661C>G (p.Leu221Val) (rs886039456)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255269 SCV000322015 likely pathogenic not provided 2017-12-05 criteria provided, single submitter clinical testing The L221V variant in the SCN1A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L221V variant was not observed in approximately 6500 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 L221V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position within the transmembrane segment S4 voltage sensor of the first homologous domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (T217K, F218L, A223E, K225N, T226K, T226R, T226M) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The L221V variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Fulgent Genetics,Fulgent Genetics RCV000763462 SCV000894239 likely pathogenic Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-10-31 criteria provided, single submitter clinical testing

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