ClinVar Genomic variation as it relates to human health

An R316Q variant that is likely pathogenic has been identified in the KIF1A gene. The R316Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a missense variant at the same residue (R316W) has been previously reported as a de novo substituion in an individual with mild intellectual disability, ataxia, optic nerve atrophy, cerebellar atrophy, neuropathy, and spastic paraparesis (Lee et al., 2014). The R316Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R316Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, this amino acid substitution occurs within the predicted motor domain of the protein, where all pathogenic missense KIF1A pathogenic variants have been identified to-date (Lee et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

The c.947G>A (p.Arg316Gln) variant in the KIF1A gene has not been described in the literature to our knowledge. This variant is not present in the population database (GnomAD and ABraOM), suggesting it is not a common benign variant in these populations. This variant is deposited in the ClinVar, but there is a conflict of interpretation (Variation ID: 373642), 1 star. This variant replaces arginine with glutamine at codon 316 of the KIF1A protein, which is highly conserved across different species. This variant is in an important functional domain of the protein (Kinesin motor domain). Additionally, a missense variant in the same amino acid (p.Arg316Trp) was described in two unrelated patients with a complex clinical picture characterized by global developmental delay, moderate to severe intellectual disability, optic nerve atrophy, cerebellar atrophy, ataxia, and spastic paraparesis (PMID: 25265257; PMID: 26354034). Our lab found it once, in heterozygous, in a 4-years-old female with a complex CMT2 phenotype. In summary, the p.Arg316Gln meets our criteria to be classified as likely pathogenic.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg316 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25265257, 26125038, 26354034, 28554332). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 KIF1A protein function. ClinVar contains an entry for this variant (Variation ID: 373642). This missense change has been observed in individual(s) with clinical features of autosomal dominant hereditary spastic paraplegia (PMID: 32935419, 33880452). 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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 316 of the KIF1A protein (p.Arg316Gln).

Likely pathogenicity based on finding it once in our laboratory de novo in an 8-year-old female with progressive lower extremity weakness, spastic paraplegia, neurogenic bowel and bladder (onset at 4y)