ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5121T>A (p.Phe1707Leu)

dbSNP: rs796053033
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188992 SCV000242623 likely pathogenic not provided 2020-07-22 criteria provided, single submitter clinical testing Reported in a patient with epilepsy in the published literature and at GeneDx (Lindy et al., 2018); This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the fourth homologous domain; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29655203)
Invitae RCV000806458 SCV000946460 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2019-07-11 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been observed in an individual with epilepsy and neurodevelopmental disorder (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 206858). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 1707 of the SCN1A protein (p.Phe1707Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine.

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