2-240783764-G-A
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001244008.2(KIF1A):c.773C>T(p.Thr258Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T258K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001244008.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF1A | NM_001244008.2 | c.773C>T | p.Thr258Met | missense_variant | 8/49 | ENST00000498729.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF1A | ENST00000498729.9 | c.773C>T | p.Thr258Met | missense_variant | 8/49 | 5 | NM_001244008.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1431030Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 708762
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 30 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | research | Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) | Apr 27, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Jun 15, 2020 | 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). - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 09, 2021 | 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) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 09, 2018 | - - |
Hereditary spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 02, 2021 | - - |
Neuropathy, hereditary sensory, type 2C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Oct 11, 2021 | - - |
Intellectual disability, autosomal dominant 9 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Sep 16, 2021 | - - |
Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at