ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4345C>T (p.Leu1449Phe) (rs768638174)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766760 SCV000242580 uncertain significance not provided 2014-10-23 criteria provided, single submitter clinical testing The L1449F 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. This substitution alters a conserved position between transmembrane segments 5 and 6 in the third homologous domain. Multiple missense mutations in nearby residues have been reported in association with SCN1A-related disorders, supporting the functional importance of this region of the protein. However, the L1449F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY,CHILD-EPI panel(s).
Athena Diagnostics Inc RCV000188949 SCV000615035 uncertain significance not specified 2016-08-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766760 SCV001247836 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing
Invitae RCV001211105 SCV001382628 uncertain significance Early infantile epileptic encephalopathy 2019-06-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1449 of the SCN1A protein (p.Leu1449Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs768638174, ExAC 0.002%). This variant has not been reported in the literature in individuals with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 206826). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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