ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.2774T>C (p.Met925Thr)

dbSNP: rs1057518373
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413714 SCV000491953 likely pathogenic not provided 2016-11-28 criteria provided, single submitter clinical testing A novel M925T variant that is likely pathogenic has been identified in the SCN2A gene. The M925T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M925T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the second homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001194630 SCV001364289 likely pathogenic Developmental and epileptic encephalopathy, 11 2020-02-28 criteria provided, single submitter research ACMG codes: PS2, PM2, PP3
Labcorp Genetics (formerly Invitae), Labcorp RCV002523951 SCV003459358 pathogenic Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 2022-11-28 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 373364). This missense change has been observed in individual(s) with childhood epilepsy and/or epileptic encephalopathy with cerebellar atrophy (PMID: 29720203, 34894057; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 925 of the SCN2A protein (p.Met925Thr).
Revvity Omics, Revvity RCV000413714 SCV003820780 uncertain significance not provided 2019-12-10 criteria provided, single submitter clinical testing

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