ClinVar Genomic variation as it relates to human health

This variant is interpreted as pathogenic for NESCAV syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo (paternity and maternity confirmed) (PS2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5).

Variant summary: KIF1A c.761G>A (p.Arg254Gln) results in a conservative amino acid change located in the Kinesin motor domain (IPR001752) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 210076 control chromosomes (gnomAD and publication data). c.761G>A has been reported in the literature in individuals affected with KIF1A-associated neurological disorder (Ohba_2015, Rudenskaya_2020, Boyle_2021), including one de novo occurrence. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In addition, p.Arg254 is close to the ATP binding site of KIF1A and involved in ATP and motor protein binding (CryoEM structure, Boyle_2021). Other missense substitutions at this codon (p.Arg254Pro, p.Arg254Gly and p.Arg254Trp) have been reported in affected individuals and classified as pathogenic/likely pathogenic in ClinVar database, suggesting that this arginine residue is critical for KIF1A protein function. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=6) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

Not observed in large population cohorts (gnomAD); 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: 26354034, 28332297, 30612907, 33880452, 21376300, 21820098, 26125038)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 254 of the KIF1A protein (p.Arg254Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with lower limb spasticity, ataxic gait and cerebellar atrophy (PMID: 26354034). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280500). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg254 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26354034). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Variant confirmed as disease-causing by referring clinical team