rs387907287

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_004984.4(KIF5A):c.611G>A(p.Arg204Gln) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 28)

Consequence

KIF5A
NM_004984.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.90

Variant links:

Genes affected

KIF5A (HGNC:6323): (kinesin family member 5A) This gene encodes a member of the kinesin family of proteins. Members of this family are part of a multisubunit complex that functions as a microtubule motor in intracellular organelle transport. Mutations in this gene cause autosomal dominant spastic paraplegia 10. [provided by RefSeq, Jul 2008]

KIF5A links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a region_of_interest Microtubule-binding (size 141) in uniprot entity KIF5A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_004984.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-57567514-C-T is described in Lovd as [Pathogenic].

PP2

Missense variant in the KIF5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 76 curated benign missense variants. Gene score misZ: 3.5984 (above the threshold of 3.09). Trascript score misZ: 5.0239 (above the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis, susceptibility to, 25, inherited neurodegenerative disorder, hereditary spastic paraplegia 10, myoclonus, intractable, neonatal, autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 12-57567515-G-A is Pathogenic according to our data. Variant chr12-57567515-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57567515-G-A is described in Lovd as [Likely_pathogenic]. Variant chr12-57567515-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5A	NM_004984.4 link	c.611G>A	p.Arg204Gln	missense_variant	Exon 8 of 29	ENST00000455537.7	NP_004975.2	Q12840
KIF5A	NM_001354705.2 link	c.344G>A	p.Arg115Gln	missense_variant	Exon 5 of 26		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KIF5A	ENST00000455537.7 link	c.611G>A	p.Arg204Gln	missense_variant	Exon 8 of 29	1	NM_004984.4	ENSP00000408979.2	Q12840
KIF5A	ENST00000674619.1 link	c.611G>A	p.Arg204Gln	missense_variant	Exon 8 of 30			ENSP00000502270.1	A0A6Q8PGJ3
KIF5A	ENST00000676457.1 link	c.506G>A	p.Arg169Gln	missense_variant	Exon 7 of 28			ENSP00000501588.1	A0A6Q8PEZ8
KIF5A	ENST00000286452.5 link	c.344G>A	p.Arg115Gln	missense_variant	Exon 5 of 26	2		ENSP00000286452.5	J3KNA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 26, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on ATPase rate and microtubule affinity, resulting in abnormal microtubule motility (Jennings et al., 2017); 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: 24731568, 26543653, 25008398, 27066564, 21107874, 21623771, 32319259, 22785106, 28678816, 18853458) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 10

Pathogenic:3

Aug 12, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000037129, PMID:18853458, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 21623771, 18853458, 25008398, 26543653, 24731568, PS4_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000424651, PMID:18500496, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.924, 3CNET: 0.998, PP3_P). A missense variant is a common mechanism associated with Spastic paraplegia 10 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Myoclonus, intractable, neonatal

Pathogenic:2

Sep 30, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PM5,PP3,PP5. -

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 -

KIF5A-related disorder

Pathogenic:2

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KIF5A c.611G>A variant is predicted to result in the amino acid substitution p.Arg204Gln. This variant has been reported in several individuals with spastic paraplegia (see for example, Goizet et al. 2009. PubMed ID: 18853458; Crimella et al. 2011. PubMed ID: 21623771; Jerath et al. 2015. PubMed ID: 26543653; Lee et al. 2020. PubMed ID: 32319259). This variant has not been reported in a large population database, indicating this variant is rare. Alternate nucleotide substitutions affecting the same amino acid (p.Arg204Pro and p.Arg204Trp), have also been reported in individuals with spastic paraplegia (Dufke et al. 2012. PubMed ID: 22552817; Liu et al. 2014. PubMed ID: 25008398; Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php). In summary, The c.611G>A (p.Arg204Gln) variant is interpreted as pathogenic. -

Nov 09, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KIF5A c.611G>A (p.Arg204Gln) results in a conservative amino acid change located in the Kinesin motor domain (IPR001752) of the encoded protein sequence. Switch 1 region spanning residues 199-204 is essential for phosphate binding (consensus sequence NXXSSR). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes. c.611G>A has been reported in the literature in multiple individuals affected with features of KIF5A-Related Disorders such as Herediatry Spastic Paraplegia type 10 (example, Goizet_2009, Crimella_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Jennings_2017). The most pronounced variant effect results in <10% of normal mictotubule-stimulated ATPase activity and reduced microtubule affinity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Spastic paraplegia

Pathogenic:1

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 204 of the KIF5A protein (p.Arg204Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia type 10 (SPG10) (PMID: 18853458, 21623771, 24731568, 25008398, 26543653). ClinVar contains an entry for this variant (Variation ID: 37129). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KIF5A protein function with a positive predictive value of 80%. This variant disrupts the p.Arg204 amino acid residue in KIF5A. Other variant(s) that disrupt this residue have been observed in individuals with KIF5A-related conditions (PMID: 18500496, 22552817), which suggests that this may be a clinically significant amino acid residue. 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

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

H;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.97

MutPred

0.88

Gain of catalytic residue at H201 (P = 0.0021);.;

MVP

0.98

MPC

2.3

ClinPred

1.0

GERP RS

4.6

Varity_R

0.89

gMVP

0.97

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

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