Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000686817 | SCV000814353 | pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2023-12-09 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 875 of the SCN1A protein (p.Thr875Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with generalized epilepsy with febrile seizures plus in a family (GEFS+) and borderline severe myoclonic epilepsy in infancy (SMEB) (PMID: 10742094, 23195492; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12883). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN1A function (PMID: 11567038, 12086636, 14702334). This variant disrupts the p.Thr875 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18930999, 20522430, 28192756). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV002316193 | SCV000851283 | likely pathogenic | Inborn genetic diseases | 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, |
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). |
Ce |
RCV001311218 | SCV001501311 | pathogenic | not provided | 2021-07-01 | criteria provided, single submitter | clinical testing | |
3billion | RCV000013743 | SCV002318874 | pathogenic | Generalized epilepsy with febrile seizures plus, type 2 | 2022-03-22 | criteria provided, single submitter | clinical testing | The variant has been observed in at least two similarly affected unrelated individuals (PMID: 10742094, 23195492) and has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 10742094, 23195492). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12086636, 11567038, 14702334). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.983>=0.6, 3CNET: 0.989>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:18930999). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
OMIM | RCV000013743 | SCV000033990 | pathogenic | Generalized epilepsy with febrile seizures plus, type 2 | 2000-04-01 | no assertion criteria provided | literature only | |
Uni |
RCV000059471 | SCV000090996 | not provided | Generalized epilepsy with febrile seizures plus, type 1 | no assertion provided | not provided |