Submissions for variant NM_001244008.2(KIF1A):c.560C>T (p.Thr187Ile)

gnomAD frequency: 0.00001  dbSNP: rs370623844

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502672	SCV000595406	uncertain significance	not specified	2016-02-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001066424	SCV001231433	uncertain significance	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 187 of the KIF1A protein (p.Thr187Ile). This variant is present in population databases (rs370623844, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 435631). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KIF1A protein function with a positive predictive value of 95%. 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.
Ambry Genetics	RCV002524211	SCV003546861	uncertain significance	Inborn genetic diseases	2021-03-15	criteria provided, single submitter	clinical testing	The c.560C>T (p.T187I) alteration is located in exon 6 (coding exon 5) of the KIF1A gene. This alteration results from a C to T substitution at nucleotide position 560, causing the threonine (T) at amino acid position 187 to be replaced by an isoleucine (I). The in silico prediction for the p.T187I alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV004591445	SCV005078865	uncertain significance	not provided	2023-08-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26125038, 21820098, 21376300)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000502672	SCV005204529	uncertain significance	not specified	2024-06-20	criteria provided, single submitter	clinical testing	Variant summary: KIF1A c.560C>T (p.Thr187Ile) results in a non-conservative amino acid change located in the Kinesin motor domain (IPR001752) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248932 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.560C>T in individuals affected with NESCAV Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 435631). Based on the evidence outlined above, the variant was classified as uncertain significance.