ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4970G>A (p.Arg1657His) (rs121917994)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001229900 SCV001402362 likely pathogenic Early infantile epileptic encephalopathy 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1657 of the SCN1A protein (p.Arg1657His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with early onset epilepsy (PMID: 17347258). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68559). 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.Arg1657 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 14672992), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
UniProtKB/Swiss-Prot RCV000059434 SCV000090958 not provided Focal epilepsy no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003955 SCV001161945 likely pathogenic Autistic disorder of childhood onset; Focal seizures; Microcephaly no assertion criteria provided research

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