Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001267513 | SCV001445694 | likely pathogenic | Inborn genetic diseases | 2019-08-29 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV003156334 | SCV003845807 | pathogenic | not provided | 2022-09-21 | criteria provided, single submitter | clinical testing | Not observed at significant frequency 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: 26125038, 21820098, 21376300, 29589274) |
| Laboratory for Molecular Medicine, |
RCV004017814 | SCV004848438 | likely pathogenic | Intellectual disability, autosomal dominant 9 | 2020-10-21 | criteria provided, single submitter | clinical testing | The p.Leu249Pro variant in KIF1A has been reported as de novo through trio WES in an individual with features associated with KIF1A-related neurological disorder (KAND), such as severe developmental delay, cerebellar ataxia and atrophy on MRI, spastic paraparesis, and eye findings. The individual also carried a de novo duplication of 22q11.23 that is known to demonstrate variable expression and incomplete penetrance (Demily 2018, PMID: 29589274). The p.Leu249Pro variant was also confirmed to be de novo through trio whole genome sequencing in a young woman with developmental delay, seizures, hypotonia, intellectual disability, cerebellar atrophy, and cortical visual impairment by the Broad Institute Rare Genomes Project. It was absent from large population studies. Another variant involving this codon (p.Leu249Gln) has been identified in other individuals with KIF1A-related neurological disorder (ClinVar variation ID 162061) suggesting that changes at this codon are not tolerated. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in this region of the KIF1A gene in the general population is lower than expected, suggesting that a missense variant in this region may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant KIF1A-related neurological disorder. ACMG/AMP Criteria applied: PS2, PM2_Supporting, PM5_Supporting, PP2, PP3 |