rs797045655

Variant names:

• chr2-240783087-G-A
• rs797045655
• NM_001244008.2:c.821C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001244008.2(KIF1A):​c.821C>T​(p.Ser274Leu) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S274S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.75
• Publications: 8 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 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001244008.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 2-240783087-G-A is Pathogenic according to our data. Variant chr2-240783087-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 211298.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.821C>T	p.Ser274Leu	missense_variant	Exon 9 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.821C>T	p.Ser274Leu	missense_variant	Exon 9 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 30 Pathogenic:4

-

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 -

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Both loss and gain of function mechanisms have been reported for variants causing spastic paraplesia (PMID: 31488895, PMID: 31455732). However neuropathy has been reported to be caused by loss of function variants only (PMID: 22258533). (N) 0104 - Dominant negative is a mechanism of disease for this gene. Missense clustering within the kinesin domain have been shown to cause NESCAV syndrome due to a dominant negative disease mechanism (PMID: 28970574). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Missense variants and variants resulting in a premature termination codon have been reported to cause dominant and recessive disease. Missense variants found within the kinesin domain are likely to cause a dominant form of disease (PMID: 31488895, PMID: 31455732, PMID: 28970574). (N) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine (exon 9). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region) (kinesin domain; PDB, NCBI). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been report once as de novo in an individual with intellectual disability, and in another individual with a KIF1A-related condition (ClinVar, LOVD). It has also been reported in a severely affected individual with a dominant condition, however the exact phenotype of this individual is unclear (Conference poster; Boyle, (2019)). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:2

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate impaired microtubule binding (Boyle L et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33880452, 26125038, 21376300, 21820098) -

Hereditary spastic paraplegia Pathogenic:1

Aug 15, 2024

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant results in a change from serine to tryptophan at amino acid position 274. It has been previously reported in individuals with KIF1A-related disorders (PMID: 33880452). Functional studies support that this variant impairs kinesin motor activity (PMID: 33880452). This variant has not been observed in population controls of the Genome Aggregation Database (gnomAD). In silico prediction programs predict this variant to impact protein function. Based on the evidence above, this variant is classified as pathogenic (PS3, PS2, PS4_M, PM2, PM1, PP3, PP5). -

Intellectual disability, autosomal dominant 9 Pathogenic:1

Oct 23, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 20, 2023

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 274 of the KIF1A protein (p.Ser274Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant KIF1A-related conditions (PMID: 33880452; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 211298). 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	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.7	H;H;.;.;.;.;.;H;.;.;.;H;.
PhyloP100		9.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.9	.;D;D;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0010	.;D;D;.;.;.;.;.;.;.;.;.;.
Polyphen		0.81	P;.;.;.;.;.;.;P;.;.;.;B;.
Vest4		0.96, 0.97
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		3.5
PromoterAI		-0.028	Neutral
Varity_R		0.93
gMVP		1.0
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797045655; hg19: chr2-241722504; COSMIC: COSV57486594;