rs786200949

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_001244008.2(KIF1A):​c.206C>T​(p.Ser69Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S69W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KIF1A
NM_001244008.2 missense

Scores

3
14
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.22

Publications

12 publications found
Variant links:
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]
KIF1A Gene-Disease associations (from GenCC):
  • intellectual disability, autosomal dominant 9
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
  • syndromic intellectual disability
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • neuropathy, hereditary sensory, type 2C
    Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • hereditary spastic paraplegia 30
    Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
  • autosomal dominant non-syndromic intellectual disability
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • PEHO syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary sensory and autonomic neuropathy type 2
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001244008.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-240788208-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 989188.Status of the report is criteria_provided_single_submitter, 1 stars.
PP5
Variant 2-240788208-G-A is Pathogenic according to our data. Variant chr2-240788208-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF1ANM_001244008.2 linkc.206C>T p.Ser69Leu missense_variant Exon 4 of 49 ENST00000498729.9 NP_001230937.1 Q12756-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIF1AENST00000498729.9 linkc.206C>T p.Ser69Leu missense_variant Exon 4 of 49 5 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 30 Pathogenic:3
Jun 15, 2020
SIB Swiss Institute of Bioinformatics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method: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); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to moderate); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1 moderate); Assumed de novo, but no confirmation of paternity and maternity (PM6); 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); -

-
Paris Brain Institute, Inserm - ICM
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 14, 2015
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Hereditary spastic paraplegia Pathogenic:1
Oct 27, 2014
Neuromuscular disorders lab, University of Helsinki
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

not provided Pathogenic:1
Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

KIF1A: PP1:Strong, PM1, PM2, PS4:Moderate, PM6:Supporting, PP2 -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1
Aug 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 69 of the KIF1A protein (p.Ser69Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with uncomplicated hereditary spastic paraplegia (PMID: 25585697, 26410750). 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: 188057). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Uncertain
0.69
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.54
D
MutationAssessor
Uncertain
2.5
M;M;.;.;.;.;.;M;.;.;.;M;.;.
PhyloP100
6.2
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-4.2
.;D;D;.;.;.;.;.;.;.;.;D;.;.
REVEL
Uncertain
0.58
Sift
Uncertain
0.0020
.;D;D;.;.;.;.;.;.;.;.;D;.;.
Sift4G
Uncertain
0.0090
.;D;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen
0.96
D;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4
0.90, 0.76
MutPred
0.40
Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);
MVP
0.84
MPC
1.5
ClinPred
0.98
D
GERP RS
4.8
Varity_R
0.43
gMVP
0.98
Mutation Taster
=11/89
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs786200949; hg19: chr2-241727625; API