NM_001244008.2:c.646C>T

Variant names:

• chr2-240785063-G-A
• rs797045164
• NM_001244008.2:c.646C>T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001244008.2(KIF1A):​c.646C>T​(p.Arg216Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.63

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]

ACMG classification

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 chr2-240785062-C-T is described in Lovd as [Likely_pathogenic].
• 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, 0.991
• PP5: Variant 2-240785063-G-A is Pathogenic according to our data. Variant chr2-240785063-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240785063-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.646C>T	p.Arg216Cys	missense_variant	Exon 7 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.646C>T	p.Arg216Cys	missense_variant	Exon 7 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 30 Pathogenic:3

Jan 01, 2022

Provincial Medical Genetics Program of British Columbia, University of British Columbia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 9 Pathogenic:2

Jun 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 13, 2021

Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

May 31, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on kinesin motility (Esmaeeli Nieh et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26125038, 32737135, 31785789, 31805580, 34015165, 25533962, 28191890, 31616253, 32935419, 33880452, 21820098, 21376300) -

Syndromic intellectual disability Pathogenic:1

May 20, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KIF1A c.646C>T (p.Arg216Cys) variant is a missense variant that is located in the conserved kinesin motor domain of KIF1A. A de novo occurrence of the p.Arg216Cys variant has been reported in association with progressive encephalopathy and brain atrophy in a two-year-old girl with severe global developmental delay, cortical visual impairment, hypotonia, hyperreflexia, spastic paraparesis, regression, athetoid movements and scoliosis (Esmaeeli Nieh et al. 2015). Additionally, two other amino acid substitutions at the same residue, c.647G>C (p.Arg216Phe) (Lee et al. 2015) and c.647G>A (p.Arg216His) (Esmaeeli Nieh et al. 2015), have been reported to arise de novo in individuals with global developmental delay, paraparesis, cerebellar signs, and other features. The p.Arg216Cys variant is not reported in the Genome Aggregation Database (version 2.1.1 and version 3.1.1) despite its location in a region of good sequence coverage, which suggests the variant is rare. Functional studies demonstrated impaired KIF1A motility in vitro (Esmaeeli Nieh et al. 2015). Based on the collective evidence, the p.Arg216Cys variant is classified as pathogenic for syndromic intellectual disability. -

Inborn genetic diseases Pathogenic:1

Feb 16, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646C>T (p.R216C) alteration is located in exon 7 (coding exon 6) of the KIF1A gene. This alteration results from a C to T substitution at nucleotide position 646, causing the arginine (R) at amino acid position 216 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in multiple unrelated patients with features consistent with KIF1A-related neurodevelopmental disorder (Deciphering Developmental Disorders, 2015; Esmaeeli Nieh, 2015; Van Beusichem, 2020; Boyle, 2021). In addition, two missense alterations affecting the same amino acid, p.R216H and p.R216P, were reported in similarly affected patients (Esmaeeli Nieh, 2015; Lee, 2015; Boyle, 2021). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is located within the kinesin motor domain and there are multiple nearby variants that are reported to be disease causing. In vitro microtubule gliding assays showed that the p.R216C variant abolishes KIF1A motility (Esmaeeli Nieh, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects KIF1A function (PMID: 26125038). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 216 of the KIF1A protein (p.Arg216Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with progressive encephalopathy and brain atrophy leading to autosomal dominant complicated hereditary spastic paraplegia (PMID: 26125038). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208160). 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.Arg216 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26125038). 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. -

PEHO syndrome Pathogenic:1

Aug 07, 2015

Child and Family Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;H;.;.;.;.;.;H;.;.;.;H;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.8	.;D;D;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.;.;D;.
Vest4		0.98, 0.98
MutPred		0.94		Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);
MVP		0.97
MPC		2.8
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.90
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

Other links and lift over

dbSNP: rs797045164; hg19: chr2-241724480; COSMIC: COSV57482306; COSMIC: COSV57482306;