2-240797715-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM5PP2PP3_StrongPP5_Very_Strong

The NM_001244008.2(KIF1A):c.38G>A(p.Arg13His) variant causes a missense change involving the alteration of a conserved nucleotide. 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. R13C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.65

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-240797716-G-A is described in Lovd as [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, 0.969

PP5

Variant 2-240797715-C-T is Pathogenic according to our data. Variant chr2-240797715-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209165.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 link	c.38G>A	p.Arg13His	missense_variant	Exon 2 of 49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.38G>A	p.Arg13His	missense_variant	Exon 2 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152178

Hom.:

Cov.:

FAILED QC

Gnomad AFR

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0.00

Gnomad AMI

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0.00

Gnomad AMR

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0.00

Gnomad ASJ

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0.00

Gnomad EAS

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0.00

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0.00

Gnomad FIN

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0.00

Gnomad MID

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0.00

Gnomad NFE

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0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726052

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

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0.00

Gnomad4 ASJ exome

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0.00

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0.00

Gnomad4 FIN exome

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0.00

Gnomad4 NFE exome

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0.00

Gnomad4 OTH exome

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0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

Gnomad4 AFR

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0.00

Gnomad4 AMR

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0.00

Gnomad4 ASJ

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0.00

Gnomad4 EAS

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0.00

Gnomad4 SAS

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0.00

Gnomad4 FIN

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0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jan 09, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency 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: 28834584, 26125038, 21820098, 21376300, 26633545, 35303589, 33880452, 34630504) -

May 10, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KIF1A: PS2, PM1, PM2, PM5, PS4:Moderate, PP2, PP3, PS3:Supporting -

Spastic paraplegia

Pathogenic:1

Jul 19, 2013

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory de novo in a 19-year-old female with motor delays, ADHD, learning disabilities, and spastic diplegia -

Intellectual disability, autosomal dominant 9

Pathogenic:1

Jul 16, 2023

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_v1.3.4, 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 of function 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) (PMIDs: 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 histidine. (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) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants at the start of the kinesin motor domain (DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Arg13Leu), p.(Arg13Ser) and p.(Arg13Cys) have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by several clinical laboratories in ClinVar and has been observed in several individuals with hereditary spastic paraplegia or intellectual disability in the literature, including several de novo cases (PMIDs: 35303589, 34630504, 28834584, 35322241). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have shown this variant disrupts the ability of KIF1A to bind to microtubules and prevents mobility of its motors (PMID: 33880452). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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 -

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

Pathogenic:1

Feb 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 209165). This missense change has been observed in individual(s) with KIF1A-related conditions (PMID: 28834584; ClinVarVariationID209165). 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 histidine, which is basic and polar, at codon 13 of the KIF1A protein (p.Arg13His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

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

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.2

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

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.93, 0.94

MutPred

0.84

Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);Loss of disorder (P = 0.0369);

MVP

0.96

MPC

2.6

ClinPred

1.0

GERP RS

4.8

Varity_R

0.93

gMVP

0.99

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