2-240775863-G-A

Position:

• chr2-240775863-G-A

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.946C>T​(p.Arg316Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R316Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 2.70

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 (HGNC:):

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 chr2-240775862-C-T is described in Lovd as [Likely_pathogenic].
• 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, 0.95
• PP5: Variant 2-240775863-G-A is Pathogenic according to our data. Variant chr2-240775863-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240775863-G-A is described in Lovd as [Pathogenic]. Variant chr2-240775863-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.946C>T	p.Arg316Trp	missense_variant	11/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.946C>T	p.Arg316Trp	missense_variant	11/49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	CHU Sainte-Justine Research Center, University of Montreal	Jan 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Dominant negative effect has been shown to cause NESCAV syndrome (MIM#614255; OMIM). Both loss and gain of function mechanisms have been reported for variants causing spastic paraplegia (MIM#610357, MIM#610357) and hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM#614213) (PMID 31488895, 31455732). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Genotype-phenotype correlation is currently unestablished. Missense variants tend to cluster within the kinesin motor domain and have been reported for both SPG30 and NESCAV syndrome. Only the correlation for HSAN2 (MIM#614213) is established with all patients except for one, carrying null variants outside the motor domain (PMID: 32737135). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been found as a de novo variant in several NESCAV patients and has been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 25265257, 26354034, 31700678). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 11, 2016	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2022	Not observed 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: 28554332, 25265257, 26354034, 26125038, 31216405, 21820098, 21376300, 32860008, 31805580, 30612907, 33880452) -

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2022	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 162060). This missense change has been observed in individual(s) with autosomal dominant KIF1A-related conditions (PMID: 25265257, 26125038, 26354034). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 316 of the KIF1A protein (p.Arg316Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2018

The p.R316W pathogenic mutation (also known as c.946C>T), located in coding exon 10 of the KIF1A gene, results from a C to T substitution at nucleotide position 946. The arginine at codon 316 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported as de novo in the heterozygous state in multiple individuals with developmental delay, intellectual disability, cerebellar atrophy, spasticity, and optic nerve atrophy (Lee JR et al. Hum. Mutat., 2015 Jan;36:69-78; Bowling KM et al. Genome Med, 2017 05;9:43; Ohba C et al. J. Hum. Genet., 2015 Dec;60:739-42). Based on supporting evidence, p.R316W is interpreted as a disease-causing mutation. -

Neuropathy, hereditary sensory and autonomic, type 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 30, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,. -

Hereditary spastic paraplegia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Hereditary spastic paraplegia 30 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 16, 2018

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as de novo in patients with developmental delay, spasticity, ataxia, cerebellar atrophy, optic atrophy, and other symptoms [PMID 25265257, 28554332, 26354034] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.;.;M;.;.;.;.;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.0	.;D;D;.;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.;.;.;D;.
Vest4		0.96, 0.93
MutPred		0.74		Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);.;Gain of catalytic residue at L314 (P = 0.0103);Gain of catalytic residue at L314 (P = 0.0103);
MVP		0.85
MPC		2.5
ClinPred		0.99	D
GERP RS		2.4
Varity_R		0.85
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs672601370; hg19: chr2-241715280;