ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.337C>A (p.Pro113Thr) (rs794726711)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Bioinformatics, Peking University RCV000180815 SCV000221777 pathogenic Severe myoclonic epilepsy in infancy 2014-12-20 criteria provided, single submitter research
GeneDx RCV000188831 SCV000242460 pathogenic not provided 2017-07-13 criteria provided, single submitter clinical testing p.Pro113Thr (CCC>ACC): c.337 C>A in exon 2 of the SCN1A gene (NM_001165963.1) The Pro113Thr missense change 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 variant is a non-conservative amino acid substitution of a non-polar Proline residue with a polar Threonine residue and the loss of a Proline may affect the secondary structure of the SCN1A protein. Pro113Thr alters a highly conserved position in the N-terminal region of the protein and multiple missense mutations at nearby codons have been reported in association with an SCN1A-related disorder. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, Pro113Thr is a strong candidate for a disease-causing mutation. This variant has been observed de novo without verified parentage. The variant is found in INFANT-EPI panel(s).
Invitae RCV000636365 SCV000757804 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2019-06-21 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 113 of the SCN1A protein (p.Pro113Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with Dravet syndrome and epileptic encephalopathy (PMID: 26096185, 25818041). ClinVar contains an entry for this variant (Variation ID: 189862). 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. For these reasons, this variant has been classified as Pathogenic.

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