ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.3434C>T (p.Thr1145Met)

gnomAD frequency: 0.00001  dbSNP: rs796053128
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189135 SCV000242767 uncertain significance not provided 2021-12-28 criteria provided, single submitter clinical testing Reported in a cohort of individuals with with epilepsy and neurodevelopmental disorders (Lindy et al., 2018); This substitution is predicted to be within the C-terminal cytoplasmic domain; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29655203)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000189135 SCV002583627 uncertain significance not provided 2022-08-16 criteria provided, single submitter clinical testing PM2, PP2, PP3
Labcorp Genetics (formerly Invitae), Labcorp RCV002517012 SCV003520127 uncertain significance Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 2023-11-27 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 1145 of the SCN2A protein (p.Thr1145Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SCN2A-related conditions (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 206986). 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 SCN2A protein function with a positive 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.

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