Submissions for variant NM_001244008.2(KIF1A):c.296C>T (p.Thr99Met)

dbSNP: rs387906799

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Child and Family Research Institute	RCV000207102	SCV000243778	pathogenic	PEHO syndrome	2015-08-06	criteria provided, single submitter	literature only
GeneDx	RCV000235916	SCV000292594	pathogenic	not provided	2022-12-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, impairing the ability of the protein to localize to distal aspects of neurites (Lee et al., 2015; Hamdan et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32737135, 26486474, 31785789, 21376300, 25253658, 25265257, 26125038, 32652677, 33753861, 33880452, 31069529, 21820098)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690609	SCV000818304	pathogenic	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 99 of the KIF1A protein (p.Thr99Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KIF1A-related conditions (PMID: 21376300, 25253658, 25265257, 26125038, 26486474). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30169). 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%. Experimental studies have shown that this missense change affects KIF1A function (PMID: 21376300, 25265257, 26125038). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000023087	SCV001430572	pathogenic	Intellectual disability, autosomal dominant 9	2016-03-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000235916	SCV002016376	pathogenic	not provided	2021-01-08	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000023087	SCV002059112	pathogenic	Intellectual disability, autosomal dominant 9	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (3billion dataset, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030169, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.933, 3CNET: 0.995, PP3_P). A missense variant is a common mechanism associated with NESCAV syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Molecular Medicine, University of Pavia	RCV000023087	SCV004026604	pathogenic	Intellectual disability, autosomal dominant 9	2023-07-28	criteria provided, single submitter	research
OMIM	RCV000023087	SCV000044378	pathogenic	Intellectual disability, autosomal dominant 9	2015-06-01	no assertion criteria provided	literature only
CHU Sainte-Justine Research Center, University of Montreal	RCV000023087	SCV000196119	pathogenic	Intellectual disability, autosomal dominant 9	2014-01-01	no assertion criteria provided	research	de novo mutation seen in 2 unrelated patients with a similar phenotype
PreventionGenetics, part of Exact Sciences	RCV004541014	SCV004800386	pathogenic	KIF1A-related disorder	2024-03-05	no assertion criteria provided	clinical testing	The KIF1A c.296C>T variant is predicted to result in the amino acid substitution p.Thr99Met. This variant has been reported as a recurrent de novo finding in individuals affected with autosomal dominant KIF1A related disorders (Hamdan et al. 2011. PubMed ID: 21376300; Okamoto et al. 2014. PubMed ID: 25253658; Langlois et al. 2016. PubMed ID: 26486474; Kaur et al. 2020. PubMed ID: 32652677; Nicita et al. 2020. PubMed ID: 32737135; Boyle et al. 2021. PubMed ID: 33880452; Paprocka et al. 2023. PubMed ID: 37239332). Functional studies have found this variant disrupts the ATP-binding site of the KIF1A motor domain, leading to a complete loss of motor function (Lee et al. 2015. PubMed ID: 25265257; Esmaeeli Nieh et al. 2015. PubMed ID: 26125038; Boyle et al. 2021. PubMed ID: 33880452). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.