rs786200949

Variant names:

• chr2-240788208-G-A
• rs786200949
• NM_001244008.2:c.206C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240788208-G-A
• chr2-240788208-G-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.22
• Publications: 12 publications found

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

ACMG classification

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
KIF1A	NM_001244008.2	c.206C>T	p.Ser69Leu	missense_variant	Exon 4 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.206C>T	p.Ser69Leu	missense_variant	Exon 4 of 49	5	NM_001244008.2	ENSP00000438388.1

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

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

Other links and lift over

dbSNP: rs786200949; hg19: chr2-241727625;