ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.784C>T (p.Arg262Trp)

gnomAD frequency: 0.00001  dbSNP: rs375711140
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001767664 SCV001998581 uncertain significance not provided 2023-01-09 criteria provided, single submitter clinical testing 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
Labcorp Genetics (formerly Invitae), Labcorp RCV001868485 SCV002260727 likely pathogenic Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5 2024-02-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 262 of the KCNT1 protein (p.Arg262Trp). This variant is present in population databases (rs375711140, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with KCNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1310550). 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 KCNT1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg262 amino acid residue in KCNT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26122718; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV001767664 SCV004699019 uncertain significance not provided 2024-02-01 criteria provided, single submitter clinical testing KCNT1: PM5, PM2:Supporting, PP3

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