ClinVar Miner

Submissions for variant NM_004321.7(KIF1A):c.761G>A (p.Arg254Gln) (rs886041692)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000326247 SCV000330423 pathogenic not provided 2016-08-05 criteria provided, single submitter clinical testing The R254Q pathogenic variant in the KIF1A gene has been reported previously as a confirmed denovo variant in an individual with lower limb spasticity, cerebellar atrophy and other findings (Ohba etal., 2015). The R254Q variant was not observed in approximately 6300 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. The R254Q variant is a semi-conservative amino acidsubstitution, 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 thisvariant is probably damaging to the protein structure/function. The R254Q variant is located in thekinesin motor domain. A different missense variant at the same codon (R254W) has been reported inassociation with intellectual disability, cerebellar atrophy, lower limb spasticity and visual disturbance(Ohba et al., 2015), supporting the functional importance of this region of the protein. We interpretR254Q as a pathogenic variant
Invitae RCV000803981 SCV000943870 pathogenic Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Intellectual disability, autosomal dominant 9 2019-05-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 254 of the KIF1A protein (p.Arg254Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected lower limb spasticity, ataxic gait and cerebellar atrophy (PMID: 26354034). ClinVar contains an entry for this variant (Variation ID: 280500). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the p.Arg254 amino acid residue in KIF1A have been observed in affected individuals (PMID: 26354034). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV001078149 SCV001426706 pathogenic Intellectual disability, autosomal dominant 9 2020-06-15 criteria provided, single submitter curation 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).
Institute of Human Genetics, University of Leipzig Medical Center RCV001078149 SCV001428463 likely pathogenic Intellectual disability, autosomal dominant 9 2019-04-26 criteria provided, single submitter clinical testing
OMIM RCV001078149 SCV001244200 pathogenic Intellectual disability, autosomal dominant 9 2020-04-16 no assertion criteria provided literature only

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