Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV003448608 | SCV004176137 | likely pathogenic | Intellectual disability, autosomal dominant 9 | 2023-08-28 | criteria provided, single submitter | clinical testing | The c.278_307del variant identified in KIF1A has not previously been reported in the literature or public variant repositories (ClinVar and LOVD), and is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.278_307del variant is located in exon 4 of this 49-exon gene and predicted to result in loss of evolutionarily conserved ten amino acids between positions 93 to 102 (p.(Ile93_Gly102del)) and disrupt the ATP-binding cassette (aa97-104) of the kinesin motor domain (aa 3-362) in the encoded protein [PMID: 26125038]. Three missense variants (p.(Thr99Met), p.(Gly102Asp), p.(Gly102Ser)) within the predicted deleted region have been reported in heterozygous state in individuals with KIF1A-related disorders with p.(Thr99Met) variant being a hot-spot variant reported in at least 10 individuals [PMID: 21376300, 25253658, 25265257, 26125038, 26410750, 32652677, 33880452]. Functional studies demonstrated the importance of the p.Thr99 and p.Gly102 residues in binding and movement functions of the motor domain [PMID: 26125038, 25265257]; however, missense variation and loss of these residues might show different effects. While the c.278_307del variant is observed at an alternate allele frequency supporting heterozygosity in this sample, the variant is also present in ~10% of the reads from a parental sample, suggesting this variant is inherited from the parent with low-level mosaicim. Based on available evidence this c.278_307del p.(Ile93_Gly102del) variant identified in KIF1A is classified as Likely Pathogenic. |
| Labcorp Genetics |
RCV003778498 | SCV004592069 | uncertain significance | Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9 | 2023-08-17 | criteria provided, single submitter | clinical testing | This variant, c.278_307del, results in the deletion of 10 amino acid(s) of the KIF1A protein (p.Ile93_Gly102del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |