ClinVar Genomic variation as it relates to human health

[ACMG/AMP: PS2, PM1, PM2, PP2, PP3, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29720203, 25785782, 25326637, 29186148, 27779742, 28923014, 31302675, 32090326, 32139178, 32695065, 32371413, 34426522, 32969205)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 850 of the SCN8A protein (p.Arg850Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 25785782, 27779742, 28923014, 29186148, 29720203). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 135651). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg850 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been observed in individuals with SCN8A-related conditions (PMID: 30171078), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

This variant is interpreted as Pathogenic for developmental and epileptic encephalopathy 13. This missense change is absent from large population cohorts (gnomAD v4.1.0 PM2_supporting); it has been observed as de novo variant in multiple unrelated individuals with epileptic encephalopathies (PMID: 25785782; 27779742; 29720203 PS2_strong and PS4_moderate); computational evidence strongly support a damaging effect on gene or gene product (Revel 0,987 PP3_Strong); functional assays show that the variant affects channel properties and function (PMID: 31715021 PS3_moderate).

The p.R850Q pathogenic mutation (also known as c.2549G>A), located in coding exon 15 of the SCN8A gene, results from a G to A substitution at nucleotide position 2549. The arginine at codon 850 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected as de novo occurrences in several individuals with early infantile epileptic encephalopathy (EIEE) and non specific epileptic encephalopathies as well as in one individual with severe childhood epilepsy (Kong W et al. Epilepsia, 2015 Mar;56:431-8; Zhang Q et al. Clin. Genet., 2017 May;91:717-724; Stank D et al. Orphanet J Rare Dis, 2018 May;13:71; Zhu X et al. PLoS Genet., 2017 Nov;13:e1007104). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.