rs879253888
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001244008.2(KIF1A):c.760C>T(p.Arg254Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R254Q) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
KIF1A
NM_001244008.2 missense
NM_001244008.2 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 3.04
Genes affected
KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-240783776-C-T is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1A. . Gene score misZ 5.1579 (greater than the threshold 3.09). Trascript score misZ 5.0191 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
Variant 2-240783777-G-A is Pathogenic according to our data. Variant chr2-240783777-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 245636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240783777-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| KIF1A | NM_001244008.2 | c.760C>T | p.Arg254Trp | missense_variant | 8/49 | ENST00000498729.9 | NP_001230937.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KIF1A | ENST00000498729.9 | c.760C>T | p.Arg254Trp | missense_variant | 8/49 | 5 | NM_001244008.2 | ENSP00000438388.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000139 AC: 2AN: 1435200Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 2AN XY: 711278
GnomAD4 exome
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2
AN:
1435200
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31
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2
AN XY:
711278
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 9 Pathogenic:4
| Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Jun 15, 2020 | This variant is interpreted as pathogenic for NESCAV syndrome, 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); De novo (paternity and maternity confirmed) (PS2); 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); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1 downgraded to supporting); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to supporting). - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000245636). Different missense changes at the same codon (p.Arg254Gln, p.Arg254Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280500, VCV000392042). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jan 30, 2018 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); Published functional studies demonstrate that the variant results in impaired microtubule-based motility (Boyle et al., 2021); This variant is associated with the following publications: (PMID: 26354034, 28332297, 30612907, 33619735, 21376300, 26125038, 21820098, 30564185, 33880452, 32096284) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | KIF1A: PM2, PM5, PS2:Moderate, PS4:Moderate, PP2, PP3 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 08, 2017 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 19, 2016 | - - |
KIF1A-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 09, 2024 | The KIF1A c.760C>T variant is predicted to result in the amino acid substitution p.Arg254Trp. This variant has been reported as a de novo finding in multiple individuals with autosomal dominant neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment (NESCAV) syndrome (Ohba et al. 2015. PubMed ID: 26354034; Sakamoto et al. 2022. PubMed ID: 36305856; Kim et al. 2023. PubMed ID: 37180992). This variant has not been reported in a large population database, indicating it is rare. An in vitro experimental study suggests this variant affects the KIF1A motor function (Boyle et al. 2021. PubMed ID: 33880452). An alternate missense change affecting the same amino acid (p.Arg254Gln) has been reported de novo in an individual with NESCAV syndrome (Ohba et al. 2015. PubMed ID: 26354034). In summary, the c.760C>T (p.Arg254Trp) variant is interpreted as pathogenic. - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 254 of the KIF1A protein (p.Arg254Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant hereditary spastic paraplegia (PMID: 26354034, 30564185). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 245636). 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. This variant disrupts the p.Arg254 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26354034). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Neuropathy, hereditary sensory and autonomic, type 2A;C3280168:Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;.;.;.;.;.;H;.;.;.;H;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D;D;.;.;.;.;.;.;.;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;D;D;.;.;.;.;.;.;.;.;D;.
Sift4G
Pathogenic
.;D;D;.;.;.;.;.;.;.;.;.;.
Polyphen
D;.;.;.;.;.;.;D;.;.;.;D;.
Vest4
0.95, 0.96
MutPred
Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);
MVP
0.83
MPC
2.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at