2-240775889-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001244008.2(KIF1A):​c.920G>A​(p.Arg307Gln) 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. R307G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KIF1A
NM_001244008.2 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.71
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr2-240775890-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435636.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in the KIF1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 112 curated pathogenic missense variants (we use a threshold of 10). The gene has 150 curated benign missense variants. Gene score misZ: 5.1579 (above the threshold of 3.09). Trascript score misZ: 5.0191 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.99
PP5
Variant 2-240775889-C-T is Pathogenic according to our data. Variant chr2-240775889-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240775889-C-T is described in Lovd as [Pathogenic]. Variant chr2-240775889-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF1ANM_001244008.2 linkc.920G>A p.Arg307Gln missense_variant Exon 11 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.920G>A p.Arg307Gln missense_variant Exon 11 of 49 5 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1460308
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
726556
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Pathogenic:5
Jan 06, 2017
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

neurodegenerative syndrome; Intellectual disability; hypotonia; cerebellar atrophy; optic nerve atrophy; congenital retinal dystrophy; pyramidal syndrome (Rossolimo and Babinsky signs) -

Dec 03, 2018
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

The heterozyous p.Arg307Gln variant in KIF1A was identified by our study in one individual with GLUT1 deficiency syndrome. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies and is predicted to shorten the length of the protein by three residues due to an in-frame deletion. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu209_Pro211del variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS2, PM4, PP3 (Richards 2015). -

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 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); 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); De novo (paternity and maternity confirmed) (PS2). -

-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.920G>A (p.Arg307Gln) missense variant in KIF1A gene has been reported in individuals affected with intellectual disability, cerebellar atrophy, spasticity and optic atrophy (Hotchkiss et al., 2016; Ohba et al., 2015), and an individual with neurodevelopmental disorder (Chérot et al., 2018). The p.Arg307Gln variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/Likely Pathogenic. The amino acid Arg at position 307 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg307Gln in KIF1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Oct 24, 2023
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 31488895). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.93 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.94 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000418275 /PMID: 26354034 /3billion dataset). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26354034). Different missense changes at the same codon (p.Arg307Gly, p.Arg307Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000435636, VCV000869126 /PMID: 29915382, 32096284). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1
Nov 12, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26354034, 27034427, 28332297, 28708303, 28970574, 32737135, 34121983, 33880452, 31785789, 31805580, 21376300, 26125038, 21820098) -

Hereditary spastic paraplegia 30 Pathogenic:1
Jun 01, 2022
Solve-RD Consortium
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

KIF1A-related disorder Pathogenic:1
Sep 12, 2022
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The KIF1A c.920G>A variant is predicted to result in the amino acid substitution p.Arg307Gln. This variant, also referred to as c.902G>A, has been documented as de novo in multiple patients with spastic paraplegia, optic neve atrophy, brain anomalies, peripheral neuropathy, cognitive and language impairment, and motor delays (Hotchkiss et al. 2016. PubMed ID: 27034427; Patient 3 Ohba et al. 2015. PubMed ID: 26354034; Patients 8 and 9 in Nicita et al. 2020. PubMed ID: 32737135 ) and in a patient from a neurodevelopmental disorder cohort (Patient 18, Chérot et al. 2017. PubMed ID: 28708303). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted by multiple laboratories in ClinVar as pathogenic and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/418275). In addition, other variants impacting the same amino acid residue (p.Arg307Gly and p.Arg307Pro) have also been reported in a patient with cerebellar ataxia (Patient 041 in Sun et al. 2019. PubMed ID: 29915382) and in twins with brain anomalies, epilepsy, and neuropathy (Patient 5A and 5B in Nemani et al. 2020. PubMed ID: 32096284). Based on this evidence, the c.920G>A (p.Arg307Gln) variant is interpreted as pathogenic. -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1
Sep 15, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine with glutamine at codon 307 of the KIF1A protein (p.Arg307Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with KIF1A-related conditions (PMID: 26354034, 27034427, 28708303). In at least one individual the variant was observed to be de novo. This variant is also known as c.902G>A. ClinVar contains an entry for this variant (Variation ID: 418275). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.92
D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.6
H;H;.;.;.;.;.;H;.;.;.;.;H;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-3.4
.;D;D;.;.;.;.;.;.;.;.;.;D;.
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0010
.;D;D;.;.;.;.;.;.;.;.;.;D;.
Sift4G
Pathogenic
0.0
.;D;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.;D;.;.;.;.;D;.
Vest4
0.98, 0.98
MutPred
0.93
Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);.;Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);
MVP
0.95
MPC
2.6
ClinPred
1.0
D
GERP RS
4.0
Varity_R
0.88
gMVP
1.0

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.

Other links and lift over

dbSNP: rs1064793161; hg19: chr2-241715306; API