ClinVar Genomic variation as it relates to human health

The heterozygous p.Ile1545Val variant in SCN1A was identified by our study in one individual with Duane retraction syndrome, epilepsy, developmental delay, hypotonia, joint hypermobility, and craniofacial dysmorphisms, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Trio genome analysis showed this variant to be de novo. We believe this is a possible phenotype expansion for SCN1A-related epilepsy. The p.Ile1545Val variant in SCN1A has been previously reported in at least 6 individuals with SCN1A-related epilepsy (PMID: 30619928, PMID: 28202706, PMID: 17347258, PMID: 32371413, PMID: 31440721, ClinVar Accession SCV001423679.1). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 4 individuals with confirmed paternity and maternity (PMID: 30619928, PMID: 17347258, PMID: 32371413, ClinVar Accession SCV001423679.1). The p.Ile1545Val variant is located in a region of SCN1A that is essential to ion transport, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 21248271). This variant was absent from large population studies. The number of missense variants reported in SCN1A in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. This variant has also been reported in ClinVar (Variation ID: 68551) and has been interpreted as pathogenic by Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital and Invitae. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant SCN1A-related epilepsy. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4_Moderate, PM1_Supporting, PM2_Supporting, PP2 (Richards 2015).

[ACMG/AMP: PS2, PM1, PM2, PP2, PP3] 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].

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 SCN1A protein function. ClinVar contains an entry for this variant (Variation ID: 68551). This missense change has been observed in individual(s) with SCN1A-related conditions (PMID: 17347258, 28202706, 30619928). 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 valine, which is neutral and non-polar, at codon 1545 of the SCN1A protein (p.Ile1545Val).