ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5121T>A (p.Phe1707Leu) (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 2017-03-08 criteria provided, single submitter clinical testing The novel Phe1707Leu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. However, a different amino acid substitution at the same position, Phe1707Val, has been reported in association with Dravet syndrome (Harkin et al., 2007; Rodda et al., 2013). Phe1707Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or among the various ethnic groups studied in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. The amino acid substitution is conservative, as Phenylalanine and Leucine are both uncharged, non-polar amino acids. However, it alters a highly conserved position in the pore loop between the S5 and S6 segments of the fourth transmembrane domain, and many other missense mutations have been reported in this region of the protein in association with SCN1A-related disorders. Additionally, multiple in silico algorithms predict Phe1707Val is damaging to protein structure/function. Therefore, based on the currently available information, Phe1707Leu is a strong candidate for a disease-causing mutation.
Invitae RCV000806458 SCV000946460 uncertain significance Early infantile epileptic encephalopathy 2019-07-24 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). 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). 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"). 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. 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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