ClinVar Miner

Submissions for variant NM_001330260.2(SCN8A):c.3995T>C (p.Leu1332Pro)

dbSNP: rs2138904112
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3billion RCV001775228 SCV002011924 likely pathogenic Developmental and epileptic encephalopathy, 13 2021-10-02 criteria provided, single submitter clinical testing The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.966, 3Cnet: 0.965, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline
Labcorp Genetics (formerly Invitae), Labcorp RCV001885125 SCV002286380 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2023-03-23 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu1332 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been observed in individuals with SCN8A-related conditions (PMID: 27875746), which suggests that this may be a clinically significant amino acid residue. 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 SCN8A protein function. ClinVar contains an entry for this variant (Variation ID: 1320055). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 32901917). 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 leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1332 of the SCN8A protein (p.Leu1332Pro).

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