ClinVar Genomic variation as it relates to human health

The c.2624T>C variant in SCN3A is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 875 (p.Ile875Thr). The variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) with DEE (PMIDs: 29740860, 29466837) (PS2_Very Strong) and as a de novo occurrance with unconfirmed parental relationship in a least 2 individuals with DEE (PMIDs: 29286531, 28191890) (PM6_Moderate), with additional case evidence available in the literature. The variant is absent from gnomAD v2.1.1 (PM2_Supporting). Studies have observed that when expressed in mammalian cells in culture, this variant causes a gain-of-function effect on the mutant channels as evidenced by a significant leftward/hyperpolarized shift in the voltage dependence of activation, an increase in the persistent/inactivating current, and a rightward/depolarizing shift in the voltage of inactivation (PS3; PMID: 29466837). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant developmental and epilepstic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2_VS, PM6_Moderate, PM2_Supporting, PS3. (Version 1; July 7, 2023).

The I875T variant in the SCN3A gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The I875T variant was not observed in approximately 6500 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 I875T 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 position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The I875T variant is a strong candidate for a disease-causing variant, however, the possibility it may be a rare benign variant cannot be excluded.

This variant was classified as: Likely pathogenic. This variant arose de novo in at least one reported proband.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This missense change has been observed in individual(s) with polymicrogyria and early infantile epileptic encephalopathy (PMID: 29466837, 29740860; 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 isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 875 of the SCN3A protein (p.Ile875Thr). ClinVar contains an entry for this variant (Variation ID: 373960). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN3A function (PMID: 29466837). 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 SCN3A protein function.

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Loss of function effects have been shown to be associated with focal epilepsy whilst gain of function effects have been shown to be associated with epileptic encephalopathy (PMID: 29466837, 28235671). (N) 0200 - Variant is predicted to result in a missense amino acid change from an isoleucine to a threonine (exon 17). (N) 0251 - Variant is heterozygous. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0301 - Variant is absent from gnomAD. (P) 0600 - Variant is located in an annotated domain or motif (S4-S5 linker of ion transport domain II (PMID: 30146301, 29466837)). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported de novo in patients with epileptic encephalopathy with cerebral cortical development malformations (ClinVar; Decipher; PMID: 29740860, 30146301, 29466837, 30904718). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Cell lines expressing this variant demonstrated gain of function effects (PMID: 30146301, 29466837). (P) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Most common recurrent pathogenic variant; associated with treatment-resistant seizures, severe/profound developmental delay/intellectual disability, and malformation of cortical development (pachy- or polymicrogyria)