ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.2624C>T (p.Thr875Met) (rs121918623)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000686817 SCV000814353 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-10-16 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 The p.T875M variant (also known as c.2624C>T), located in coding exon 15 of the SCN1A gene, results from a C to T substitution at nucleotide position 2624. The threonine at codon 875 is replaced by methionine, an amino acid with similar properties. This variant was originally identified in eleven affected members of a family with generalized epilepsy with febrile seizures plus type 2 (Escayg A et al. Nat. Genet., 2000 Apr;24:343-5). This alteration was also reported in a patient with severe myoclonic epilepsy borderline (Wang JW et al. Epilepsy Res., 2012 Dec;102:195-200). This variant was previously reported in the SNPDatabase as rs121918623, but not in NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253103 SCV001428635 pathogenic Severe myoclonic epilepsy in infancy 2017-06-20 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed).
CeGaT Praxis fuer Humangenetik Tuebingen RCV001311218 SCV001501311 pathogenic not provided 2021-07-01 criteria provided, single submitter clinical testing
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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