ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.3968C>T (p.Pro1323Leu) (rs1057521746)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000781833 SCV000920182 uncertain significance not specified 2019-04-16 criteria provided, single submitter clinical testing Variant summary: SCN1A c.3968C>T (p.Pro1323Leu) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249714 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3968C>T in individuals affected with SCN1A-Related Seizure Disorder and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001054959 SCV001219321 uncertain significance Early infantile epileptic encephalopathy 2020-01-03 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1323 of the SCN1A protein (p.Pro1323Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. 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 conditions. 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 disrupts the p.Pro1323 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 21868258, 24472396), which suggests that this may be a clinically significant amino acid residue. 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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