rs387906799

Positions:

chr2-240788118-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_001244008.2(KIF1A):c.296C>T(p.Thr99Met) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.74

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 links:

KIF1A (HGNC:):

KIF1A links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.985

PP5

Variant 2-240788118-G-A is Pathogenic according to our data. Variant chr2-240788118-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240788118-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.296C>T	p.Thr99Met	missense_variant	4/49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 linkuse as main transcript	c.296C>T	p.Thr99Met	missense_variant	4/49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 9

Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been previously reported as de novo in a similarly affected individual (3billion dataset, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030169, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.933, 3CNET: 0.995, PP3_P). A missense variant is a common mechanism associated with NESCAV syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	research	CHU Sainte-Justine Research Center, University of Montreal	Jan 01, 2014	de novo mutation seen in 2 unrelated patients with a similar phenotype -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine, University of Pavia	Jul 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2016	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2022	Published functional studies demonstrate a damaging effect, impairing the ability of the protein to localize to distal aspects of neurites (Lee et al., 2015; Hamdan et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32737135, 26486474, 31785789, 21376300, 25253658, 25265257, 26125038, 32652677, 33753861, 33880452, 31069529, 21820098) -

KIF1A-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2024

The KIF1A c.296C>T variant is predicted to result in the amino acid substitution p.Thr99Met. This variant has been reported as a recurrent de novo finding in individuals affected with autosomal dominant KIF1A related disorders (Hamdan et al. 2011. PubMed ID: 21376300; Okamoto et al. 2014. PubMed ID: 25253658; Langlois et al. 2016. PubMed ID: 26486474; Kaur et al. 2020. PubMed ID: 32652677; Nicita et al. 2020. PubMed ID: 32737135; Boyle et al. 2021. PubMed ID: 33880452; Paprocka et al. 2023. PubMed ID: 37239332). Functional studies have found this variant disrupts the ATP-binding site of the KIF1A motor domain, leading to a complete loss of motor function (Lee et al. 2015. PubMed ID: 25265257; Esmaeeli Nieh et al. 2015. PubMed ID: 26125038; Boyle et al. 2021. PubMed ID: 33880452). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

PEHO syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

literature only

Child and Family Research Institute

Aug 06, 2015

- -

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

Jan 18, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 99 of the KIF1A protein (p.Thr99Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KIF1A-related conditions (PMID: 21376300, 25253658, 25265257, 26125038, 26486474). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30169). 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: 21376300, 25265257, 26125038). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.;.;.;.;D;.;.;.;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

.;D;D;D;D;D;.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.7

H;H;.;.;.;.;.;H;.;.;.;H;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.1

.;D;D;.;.;.;.;.;.;.;.;D;.;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

.;D;D;.;.;.;.;.;.;.;.;D;.;.

Sift4G

Pathogenic

0.0

.;D;D;.;.;.;.;.;.;.;.;.;.;.

Polyphen

1.0

D;.;.;.;.;.;.;D;.;.;.;D;.;.

Vest4

0.93, 0.92

MutPred

0.90

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.97

MPC

2.5

ClinPred

1.0

GERP RS

4.8

Varity_R

0.89

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over