ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.4730G>A (p.Cys1577Tyr) (rs1553520982)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549298 SCV000633864 uncertain significance Early infantile epileptic encephalopathy 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1588 of the SCN1A protein (p.Cys1588Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 461276). 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 identified in the SCN1A gene is located in the transmembrane D4-S2 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. The p.Cys1588 amino acid residue in SCN1A has been determined to be clinically significant (PMID: 17561957, 25818041). This suggests that variants that disrupt this residue are likely to be causative of disease. 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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