Submissions for variant NM_001244008.2(KIF1A):c.31C>T (p.Arg11Trp)

dbSNP: rs548204329

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	RCV000515907	SCV000574455	pathogenic	Hereditary spastic paraplegia	2017-03-07	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639771	SCV000761352	pathogenic	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 11 of the KIF1A protein (p.Arg11Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 28832565). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 424652). 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%. For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics	RCV001251222	SCV001426713	likely pathogenic	Hereditary spastic paraplegia 30	2020-06-15	criteria provided, single submitter	curation	This variant is interpreted as likely 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); Assumed de novo, but no confirmation of paternity and maternity (PM6); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); 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).
Ambry Genetics	RCV001266653	SCV001444829	likely pathogenic	Inborn genetic diseases	2019-10-15	criteria provided, single submitter	clinical testing	The p.R11W variant (also known as c.31C>T), located in coding exon 1 of the KIF1A gene, results from a C to T substitution at nucleotide position 31. The arginine at codon 11 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected as a de novo occurrence in an individual with intellectual disability and neuropathy onset in the first year of life (Morais S et al. Eur. J. Hum. Genet., 2017 11;25:1217-1228). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001310793	SCV001500733	pathogenic	not provided	2024-06-01	criteria provided, single submitter	clinical testing	KIF1A: PM1, PM2, PM5, PM6, PS4:Moderate, PP2, PP3
GeneDx	RCV001310793	SCV002499827	pathogenic	not provided	2024-09-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37251230, 37489029, 28832565, 31630374, 31227335, 33880452, 35032046, 26125038, 21376300, 21820098, 34487232)