ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4016C>A (p.Ala1339Asp) (rs794726789)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188940 SCV000242571 pathogenic not provided 2013-07-30 criteria provided, single submitter clinical testing p.Ala1339Asp (GCC>GAC): c.4016 C>A in exon 21 of the SCN1A gene (NM_001165963.1) The Ala1339Asp 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. The amino acid substitution is non-conservative, as an uncharged, non-polar Alanine residue is replaced by a negatively charged Aspartic acid residue. It alters a highly conserved position in the intracellular loop between the S4 and S5 segments of the third transmembrane domain of the protein, and multiple in silico algorithms predict it is damaging to protein structure/function. Additionally, a different amino acid substitution at the same position (Ala1339Val) was previously reported as a de novo mutation in association with severe myoclonic epilepsy of infancy (Wang et al., 2012). The variant is found in INFANT-EPI panel(s).
Invitae RCV001222481 SCV001394580 pathogenic Early infantile epileptic encephalopathy 2019-06-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 1339 of the SCN1A protein (p.Ala1339Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with epilepsy and neurodevelopmental disorders and has also been observed to be de novo in an individual affected with clinical features of early infantile epileptic encephalopathy (PMID: 29655203, Invitae). ClinVar contains an entry for this variant (Variation ID: 206818). 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.Ala1339 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 22092154, 23195492), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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