ClinVar Miner

Submissions for variant NM_004321.7(KIF1A):c.304G>A (p.Gly102Ser) (rs1064795534)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487011 SCV000571446 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing The G102S variant in the KIF1A gene has been reported previously as an apparently de novo variant in an individual with axonal neuropathy, spasticity and intellectual disability (Citterio et al., 2015). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G102S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This amino acid substitution occurs at a conserved position within the predicted motor domain of the protein, where all pathogenic missense variants in KIF1A have been identified to date (Lee et al., 2015). In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants at the same residue (G102D) and in a nearby residue (T99M) have been reported in the Human Gene Mutation Database in association with KIF1A-related disorders (Stenson et al., 2014; Lee et al., 2015). We interpret G102S as a pathogenic variant.
Invitae RCV000534578 SCV000651705 pathogenic Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Intellectual disability, autosomal dominant 9 2017-11-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 102 of the KIF1A protein (p.Gly102Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hereditary spastic paraparesis (PMID: 26410750). In addition, this variant has been shown to arise de novo in an individual affected with spastic diplegia (Invitae). 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. For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV001251229 SCV001426727 likely pathogenic Spastic paraplegia 30, autosomal recessive 2020-06-15 criteria provided, single submitter curation This variant is interpreted as likely pathogenic for spastic paraplegia 30, 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); Assumed de novo, but no confirmation of paternity and maternity (PM6); 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); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Located in a mutational hot spot and/or critical and well-established functional domain (located in the ATP binding region) without benign variation (PM1).
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV001251229 SCV001430918 pathogenic Spastic paraplegia 30, autosomal recessive 2020-08-24 criteria provided, single submitter research This variant was identified as de novo in an individual with spastic paraplegia.

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