ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.2591C>T (p.Thr864Met) (rs121918623)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000686817 SCV000814353 pathogenic Early infantile epileptic encephalopathy 2018-09-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 875 of the SCN1A protein (p.Thr875Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with generalized epilepsy with febrile seizures plus in a family (GEFS+) (PMID: 10742094) and has also been observed in an individual with borderline severe myoclonic epilepsy in infancy (SMEB) (PMID: 23195492) as well as siblings with clinical features of early infantile epileptic encephalopathy (EIEE) (Invitae). ClinVar contains an entry for this variant (Variation ID: 12883). Experimental studies have shown that this missense change disrupts channel inactivation, resulting in persistent inward sodium current (PMID: 12086636, 11567038, 14702334). The p.Thr875 amino acid residue in SCN1A has been determined to be clinically significant (PMID: 18930999, 28192756, 20522430). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000720406 SCV000851283 likely pathogenic History of neurodevelopmental disorder 2016-10-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
OMIM RCV000013743 SCV000033990 pathogenic Generalized epilepsy with febrile seizures plus, type 2 2000-04-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000059471 SCV000090996 not provided Generalized epilepsy with febrile seizures plus, type 1 no assertion provided not provided

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