ClinVar Miner

Submissions for variant NM_004321.7(KIF1A):c.947G>A (p.Arg316Gln) (rs749718096)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414618 SCV000492255 likely pathogenic not provided 2016-12-09 criteria provided, single submitter clinical testing An R316Q variant that is likely pathogenic has been identified in the KIF1A gene. The R316Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a missense variant at the same residue (R316W) has been previously reported as a de novo substituion in an individual with mild intellectual disability, ataxia, optic nerve atrophy, cerebellar atrophy, neuropathy, and spastic paraparesis (Lee et al., 2014). The R316Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R316Q variant is a semi-conservative amino acid substitution, 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 this variant is probably damaging to the protein structure/function. Additionally, this amino acid substitution occurs within the predicted motor domain of the protein, where all pathogenic missense KIF1A pathogenic variants have been identified to-date (Lee et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000543471 SCV000638646 uncertain significance Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Mental retardation, autosomal dominant 9 2017-12-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 316 of the KIF1A protein (p.Arg316Gln). 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 not been reported in the literature in individuals with KIF1A-related disease. ClinVar contains an entry for this variant (Variation ID: 373642). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Arg316Trp) has been determined to be pathogenic (PMID: 25265257, 26354034, 26125038, 28554332). This suggests that the arginine residue is critical for KIF1A protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Miraca Genetics Laboratories, RCV000679891 SCV000807297 uncertain significance Spastic paraplegia 2017-09-01 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it once in our laboratory de novo in an 8-year-old female with progressive lower extremity weakness, spastic paraplegia, neurogenic bowel and bladder (onset at 4y)

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