Submissions for variant NM_001244008.2(KIF1A):c.452G>A (p.Cys151Tyr)

dbSNP: rs1553638655

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522046	SCV000620371	pathogenic	not provided	2018-01-18	criteria provided, single submitter	clinical testing	The C151Y variant in the KIF1A gene, previously reported by GeneDx as a variant of uncertain significance, has not been reported previously in the literature as a pathogenic variant nor as a benign variant, to our knowledge. The C151Y variant is not observed in large population cohorts (Lek et al., 2016). The C151Y 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, this amino acid substitution does occur within the predicted motor domain of the protein, where all pathogenic missense KIF1A pathogenic variants have been identified to date (Lee et al., 2014). We interpret C151Y as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051953	SCV001216138	uncertain significance	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2024-06-12	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 151 of the KIF1A protein (p.Cys151Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 33880452; Invitae). ClinVar contains an entry for this variant (Variation ID: 451648). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
3billion, Medical Genetics	RCV001775130	SCV002011982	likely pathogenic	Intellectual disability, autosomal dominant 9	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic (VCV000451648.4, PS1_P). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.