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); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1 downgraded to supporting); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to supporting).

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000245636). Different missense changes at the same codon (p.Arg254Gln, p.Arg254Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280500, VCV000392042). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); Published functional studies demonstrate that the variant results in impaired microtubule-based motility (Boyle et al., 2021); This variant is associated with the following publications: (PMID: 26354034, 28332297, 30612907, 33619735, 21376300, 26125038, 21820098, 30564185, 33880452, 32096284)

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 254 of the KIF1A protein (p.Arg254Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant hereditary spastic paraplegia (PMID: 26354034, 30564185). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 245636). 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. 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.

KIF1A: PM2, PM5, PS2:Moderate, PS4:Moderate, PP2, PP3

The KIF1A c.760C>T variant is predicted to result in the amino acid substitution p.Arg254Trp. This variant has been reported as a de novo finding in multiple individuals with autosomal dominant neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment (NESCAV) syndrome (Ohba et al. 2015. PubMed ID: 26354034; Sakamoto et al. 2022. PubMed ID: 36305856; Kim et al. 2023. PubMed ID: 37180992). This variant has not been reported in a large population database, indicating it is rare. An in vitro experimental study suggests this variant affects the KIF1A motor function (Boyle et al. 2021. PubMed ID: 33880452). An alternate missense change affecting the same amino acid (p.Arg254Gln) has been reported de novo in an individual with NESCAV syndrome (Ohba et al. 2015. PubMed ID: 26354034). In summary, the c.760C>T (p.Arg254Trp) variant is interpreted as pathogenic.