ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.1343T>C (p.Ile448Thr)

gnomAD frequency: 0.00005  dbSNP: rs755962326
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768078 SCV000898950 uncertain significance Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-04-09 criteria provided, single submitter clinical testing SCN1A NM_001165963.1 exon 9 p.Ile448Thr (c.1343T>C): This variant has not been reported in the literature but is present in 5/30778 South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs755962326). Evolutionary conservation and computational predictive tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx RCV001568765 SCV001792691 uncertain significance not provided 2019-09-03 criteria provided, single submitter clinical testing The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the cytoplasmic loop between the first and second homologous domains
Invitae RCV001855718 SCV002183526 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2023-12-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 448 of the SCN1A protein (p.Ile448Thr). This variant is present in population databases (rs755962326, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 626009). 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 not expected to disrupt SCN1A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin RCV002287444 SCV002578167 uncertain significance Generalized epilepsy with febrile seizures plus, type 2 2022-09-27 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224425 SCV003920417 uncertain significance Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2; Developmental and epileptic encephalopathy 6B 2021-03-30 criteria provided, single submitter clinical testing SCN1A NM_001165963.1 exon 9 p.Ile448Thr (c.1343T>C): This variant has not been reported in the literature but is present in 5/30778 South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs755962326). Evolutionary conservation and computational predictive tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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