Submissions for variant NM_001244008.2(KIF1A):c.773C>T (p.Thr258Met)

dbSNP: rs1553638086

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000548642	SCV000638638	pathogenic	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2024-01-22	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 258 of the KIF1A protein (p.Thr258Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of HSP and hereditary spastic paraplegia (HSP) (PMID: 28970574; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 464261). 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: 28970574). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics	RCV001251233	SCV001426732	pathogenic	Hereditary spastic paraplegia 30	2020-06-15	criteria provided, single submitter	curation	This variant is interpreted as pathogenic for spastic paraplegia 30, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); De novo (paternity and maternity confirmed) (PS2); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to supporting); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1).
Ambry Genetics	RCV001266365	SCV001444539	likely pathogenic	Inborn genetic diseases	2018-04-09	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268098	SCV001446752	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV001251233	SCV001451088	pathogenic	Hereditary spastic paraplegia 30		criteria provided, single submitter	clinical testing
GeneDx	RCV001268098	SCV001789235	pathogenic	not provided	2021-06-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Cheon et al., 2017; Guedes-Dias et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33880452, 27535533, 32045731, 32935419, 30612907, 31488895, 28970574)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848939	SCV002105271	pathogenic	Hereditary spastic paraplegia	2021-11-02	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002289760	SCV002580424	pathogenic	Neuropathy, hereditary sensory, type 2C	2021-10-11	criteria provided, single submitter	clinical testing
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV001251233	SCV003920772	likely pathogenic	Hereditary spastic paraplegia 30	2023-04-27	criteria provided, single submitter	research
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001268098	SCV005198583	pathogenic	not provided	2023-02-13	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV001251233	SCV001760077	likely pathogenic	Hereditary spastic paraplegia 30		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV001770432	SCV002011705	pathogenic	Intellectual disability, autosomal dominant 9	2021-09-16	no assertion criteria provided	clinical testing