ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5291T>A (p.Phe1764Tyr) (rs796053037)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188998 SCV000242629 likely pathogenic not provided 2014-07-22 criteria provided, single submitter clinical testing p.Phe1764Tyr (TTC>TAC): c.5291 T>A in exon 26 of the SCN1A gene (NM_001165963.1) A F1764Y variant that is likely pathogenic has been identified in the SCNA1 gene. The F1764Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 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 F1764Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals within the predicted transmembrane S6 domain of the 4th homologous repeat of the SCN1A protein. Additionally, several missense mutations in nearby residues such as, G1762E, F1765L, Y1769H, have been reported in association with SCN1A-related disorders in an external mutation database, supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation; however, the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Invitae RCV001065456 SCV001230414 uncertain significance Early infantile epileptic encephalopathy 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with tyrosine at codon 1764 of the SCN1A protein (p.Phe1764Tyr). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a cohort of individuals tested for epielpsy and /or neurodevelopmental delay (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 206863). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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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