rs387907287

Positions:

• chr12-57567515-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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 Likely pathogenic.

• Frequency: Genomes: not found (cov: 28)
• Consequence: KIF5A NM_004984.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 ClinVar as [Likely_pathogenic]. Clinvar id is 424651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF5A. . Gene score misZ 3.5984 (greater than the threshold 3.09). Trascript score misZ 5.0239 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	UniProt
KIF5A	NM_004984.4	c.611G>A	p.Arg204Gln	missense_variant	8/29	ENST00000455537.7
KIF5A	NM_001354705.2	c.344G>A	p.Arg115Gln	missense_variant	5/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF5A	ENST00000455537.7	c.611G>A	p.Arg204Gln	missense_variant	8/29	1	NM_004984.4	P1
KIF5A	ENST00000674619.1	c.611G>A	p.Arg204Gln	missense_variant	8/30
KIF5A	ENST00000676457.1	c.506G>A	p.Arg169Gln	missense_variant	7/28
KIF5A	ENST00000286452.5	c.344G>A	p.Arg115Gln	missense_variant	5/26	2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2023	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hereditary spastic paraplegia 10 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 12, 2014	- -

KIF5A-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 20, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2022	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. -

Myoclonus, intractable, neonatal Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 30, 2019

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

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 21, 2023

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 KIF5A protein function. 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. ClinVar contains an entry for this variant (Variation ID: 37129). This missense change has been observed in individuals with hereditary spastic paraplegia type 10 (SPG10) (PMID: 18853458, 21623771, 24731568, 25008398, 26543653). This variant is not present in population databases (gnomAD no frequency). 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). -

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	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
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	D
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

Other links and lift over

dbSNP: rs387907287; hg19: chr12-57961298;