ClinVar Miner

Submissions for variant NM_004321.7(KIF1A):c.38G>A (p.Arg13His) (rs797045050)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000191098 SCV000245497 likely pathogenic Spastic paraplegia 2013-07-19 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it once in our laboratory de novo in a 19-year-old female with motor delays, ADHD, learning disabilities, and spastic diplegia
GeneDx RCV000235418 SCV000293702 pathogenic not provided 2015-12-17 criteria provided, single submitter clinical testing The R13H variant in the KIF1A gene has been reported by another clinical laboratory as de novo in one individual with learning disabilities, motor delays, spastic diplegia, and attention deficit hyperactivity disorder (Landrum et al., 2014). Numerous other de novo variants in the KIF1A gene have been observed at GeneDx in individuals with similar features, many of who had later onset of symptoms. The R13H variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R13H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position in the kinesin motor domain that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R13H as a pathogenic variant.
Invitae RCV000639795 SCV000761376 pathogenic Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Intellectual disability, autosomal dominant 9 2018-04-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 13 of the KIF1A protein (p.Arg13His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with KIF1A-related conditions (PMID: 28834584, ClinVar Variation ID: 209165). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

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