ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

In a single report (Hamdan et al., 2011 PMID: 21376300) identified a de novo heterozygous missense mutation (p.T99M) in a female patient with moderate intellectual disability. The mutation was located in a highly conserved p loop consensus ATP-binding site for the KIF1A motor domain. Primary rat hippocampal neurons transfected with eGFP fusion constructs containing the identified Thr99Met mutation displayed altered protein subcellular localization. Given that there are multiple entries in the Database for Genomic Variants (DGV) and that all previously identified missense and nonsense mutations affecting KIF1A have been associated with autosomal recessive disorders , the mutation identified by Hamdan et al, if responsible for the observed phenotype in this single individual, may result in a gain-of-function/dominant negative gene product. This gene has been given a haploinsufficiency score of 0 based on this phenotype. Of note, mutations in the KIF1A gene (OMIM: 601255) have also been described in two different clinically and genetically heterogeneous groups of autosomal recessive neurodegenerative diseases: hereditary sensory neuropathy type IIC (HSN2C, OMIM: 614213) and spastic paraplegia-30 (SPG30, OMIM: 610357). In HSN2C, all patients from four families of different origins were carriers of homozygous or compound heterozygous nonsense mutations of KIF1A. Rivi?re et al., 2011 (PMID: 21820098) identified homozygous 1 bp deletion resulting in a truncating mutation, in three affected members of an Afghan family as well as four patients from two unrelated families from Turkey and Belgium . In SPG30, homozygous missense mutations were found to cosegregate with the disease (Erlich et al., 2011 PMID: 21487076, Klebe et al., 2012 (PMID: 22258533). There is no evidence to suggest that loss of a single copy of KIF1A causes an abnormal phenotype.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There is no evidence of triplosensitivity at the time of this review.