Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001050549 | SCV001214664 | uncertain significance | Epilepsy, familial focal, with variable foci 3 | 2024-01-21 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 249 of the NPRL3 protein (p.Glu249Lys). This variant is present in population databases (rs200041907, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with focal epilepsy (PMID: 26505888, 27173016, 32086284). ClinVar contains an entry for this variant (Variation ID: 847079). 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 NPRL3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect NPRL3 function (PMID: 31639411). 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. |
Gene |
RCV001585948 | SCV001813146 | uncertain significance | not provided | 2019-03-14 | criteria provided, single submitter | clinical testing | Identified in a proband with focal epilepsy but was not present in a similarly affected sibling (Weckhuysen et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32086284, 31639411, 30093711, 27173016, 26505888) |