ClinVar Miner

Submissions for variant NM_004321.7(KIF1A):c.920G>A (p.Arg307Gln) (rs1064793161)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480291 SCV000565098 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing The R307Q variant in the KIF1A gene has been reported previously as a de novo finding in two presumably unrelated individuals with intellectual disability, spasticity, and optic nerve or cerebellar atrophy (Ohba et al., 2015; Hotchkiss et al., 2016). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R307Q 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. We interpret R307Q as a pathogenic variant.
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement,Assistance Publique Hopitaux de Paris RCV000496175 SCV000586758 pathogenic Intellectual disability, autosomal dominant 9 2017-01-06 criteria provided, single submitter clinical testing neurodegenerative syndrome; Intellectual disability; hypotonia; cerebellar atrophy; optic nerve atrophy; congenital retinal dystrophy; pyramidal syndrome (Rossolimo and Babinsky signs)
Invitae RCV000705000 SCV000833977 pathogenic Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Intellectual disability, autosomal dominant 9 2018-05-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 307 of the KIF1A protein (p.Arg307Gln). 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 individuals affected with intellectual disability, cerebellar atrophy, spasticity and optic atrophy (PMID: 26354034, 27034427), and an individual with neurodevelopmental disorder (PMID: 28708303). This variant is also known as c.902G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 418275). 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"). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000496175 SCV001164442 likely pathogenic Intellectual disability, autosomal dominant 9 2018-12-03 criteria provided, single submitter research The heterozyous p.Arg307Gln variant in KIF1A was identified by our study in one individual with GLUT1 deficiency syndrome. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies and is predicted to shorten the length of the protein by three residues due to an in-frame deletion. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu209_Pro211del variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS2, PM4, PP3 (Richards 2015).
SIB Swiss Institute of Bioinformatics RCV000496175 SCV001426722 likely pathogenic Intellectual disability, autosomal dominant 9 2020-06-15 criteria provided, single submitter curation This variant is interpreted as likely 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); 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); De novo (paternity and maternity confirmed) (PS2).

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