ClinVar Miner

Submissions for variant NM_004321.7(KIF1A):c.914C>T (p.Pro305Leu) (rs1131690804)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523291 SCV000618279 pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing The P305L variant in the KIF1A gene has not been previously published as a pathogenic variant nor as a benign variant, to our knowledge. However, the P305L variant is reported as de novo in this patient and in another individual with developmental delay, cerebellar atrophy, ataxia, and eye movement abnormalities, tested at GeneDx. The P305L variant is not observed in large population cohorts (Lek et al., 2016). The P305L 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 P305L as a pathogenic variant.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000492064 SCV000966171 pathogenic Intellectual disability, autosomal dominant 9 2018-07-03 criteria provided, single submitter clinical testing
Invitae RCV001202708 SCV001373831 likely pathogenic Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Intellectual disability, autosomal dominant 9 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 305 of the KIF1A protein (p.Pro305Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of spastic paraplegia (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 428604). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Paris Brain Institute,Inserm - ICM RCV001391606 SCV001451093 pathogenic Spastic paraplegia 30, autosomal recessive criteria provided, single submitter clinical testing
Genomic Medicine Lab, University of California San Francisco RCV000492064 SCV001572997 pathogenic Intellectual disability, autosomal dominant 9 2019-05-09 criteria provided, single submitter clinical testing
Institute for Genomic Medicine, Columbia University,Columbia University Medical Center RCV000492064 SCV000580674 likely pathogenic Intellectual disability, autosomal dominant 9 no assertion criteria provided research

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