ClinVar Miner

Submissions for variant NM_004321.7(KIF1A):c.296C>T (p.Thr99Met) (rs387906799)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Child and Family Research Institute RCV000207102 SCV000243778 pathogenic PEHO syndrome 2015-08-06 criteria provided, single submitter literature only
GeneDx RCV000235916 SCV000292594 pathogenic not provided 2015-10-06 criteria provided, single submitter clinical testing The T99M pathogenic variant in the KIF1A gene has been previously reported as a de novo, heterozygous variant in three unrelated individuals whose features include severe intellectual disability, microcephaly, epilepsy, mild ataxia, axial hypotonia, spasticity, optic atrophy, neurogenic bladder, growth failure and brain MRI abnormalities including cerebral and cerebellar atrophy (Lee et al., 2014; Okamoto et al., 2014; Hamdan et al., 2011). Additionally, functional studies have demonstrated that T99M impairs the ability of the protein to localize to distal aspects of neurites (Lee et al., 2014; Hamdan et al., 2011). The T99M variant was not observed in approximately 6500 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 T99M 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 substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T99M as a pathogenic variant.
Invitae RCV000690609 SCV000818304 pathogenic Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Intellectual disability, autosomal dominant 9 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 99 of the KIF1A protein (p.Thr99Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in many individuals affected with KIF1A-related disease (PMID: 21376300, 25265257, 25253658, 26125038, 26486474). ClinVar contains an entry for this variant (Variation ID: 30169). Experimental studies have shown that this missense change impairs distal localization in neurites and abolishes motility in vitro (PMID: 21376300, 25265257, 26125038). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000023087 SCV000044378 pathogenic Intellectual disability, autosomal dominant 9 2015-06-01 no assertion criteria provided literature only
CHU Sainte-Justine Research Center,University of Montreal RCV000023087 SCV000196119 pathogenic Intellectual disability, autosomal dominant 9 2014-01-01 no assertion criteria provided research de novo mutation seen in 2 unrelated patients with a similar phenotype

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