Submissions for variant NM_004984.4(KIF5A):c.611G>A (p.Arg204Gln)

dbSNP: rs387907287

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168349	SCV000219038	pathogenic	Spastic paraplegia	2024-11-12	criteria provided, single submitter	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196631	SCV001367251	likely pathogenic	Myoclonus, intractable, neonatal	2019-09-30	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PM5,PP3,PP5.
Paris Brain Institute, Inserm - ICM	RCV000030760	SCV001451226	pathogenic	Hereditary spastic paraplegia 10		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001682718	SCV001905654	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
3billion	RCV000030760	SCV002058320	pathogenic	Hereditary spastic paraplegia 10	2022-01-03	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468980	SCV002766278	pathogenic	KIF5A-related disorder	2022-11-09	criteria provided, single submitter	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.
GeneDx	RCV001682718	SCV003921589	pathogenic	not provided	2023-04-26	criteria provided, single submitter	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)
OMIM	RCV000030760	SCV000053421	pathogenic	Hereditary spastic paraplegia 10	2014-08-12	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV001682718	SCV001918612	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001682718	SCV001954050	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV002468980	SCV004791025	pathogenic	KIF5A-related disorder	2023-12-20	no assertion criteria provided	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.
Solve-RD Consortium	RCV001196631	SCV005091312	likely pathogenic	Myoclonus, intractable, neonatal	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team