Submissions for variant NM_004984.4(KIF5A):c.839G>A (p.Arg280His)

dbSNP: rs387907288

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	RCV000515919	SCV000574452	pathogenic	Hereditary spastic paraplegia	2017-03-07	criteria provided, single submitter	research
Athena Diagnostics	RCV001268862	SCV000613925	pathogenic	not provided	2024-08-20	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals, including a de novo case, with clinical features associated with spastic paraplegia. Multiple missense variants at this codon, including at least one considered to be pathogenic or likely pathogenic, have been reported in individuals with clinical features associated with this gene, suggesting this variant may also cause disease. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061322	SCV001226060	pathogenic	Spastic paraplegia	2022-01-06	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 18853458, 25008398, 28832565, 29892902). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37130). 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.Arg280 amino acid residue in KIF5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15452312, 18853458, 25008398). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 280 of the KIF5A protein (p.Arg280His).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268862	SCV001448070	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000030761	SCV001451234	pathogenic	Hereditary spastic paraplegia 10		criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV002051649	SCV001737094	pathogenic	Demyelinating peripheral neuropathy		criteria provided, single submitter	clinical testing
GeneDx	RCV001268862	SCV001871211	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15452312, 18853458, 25008398, 28832565, 29892902, 22785106, 33284322, 33931448, 34715294, 34983064, 28678816, 35303589)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001268862	SCV002047707	pathogenic	not provided	2021-09-27	criteria provided, single submitter	clinical testing	The KIF5A c.839G>A; p.Arg280His variant (rs387907288) is reported in the literature in multiple families affected with hereditary spastic paraplegia and Charcot-Marie-Tooth disease and has been observed segregating with disease in multiple affected family members (Goizet 2009, Liu 2014, Morais 2017, Nam 2018). This variant is reported in ClinVar (Variation ID: 37130). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 280 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.936). Additionally, other variants at this codon (c.838C>T; p.Arg280Cys, c.839G>T; p.Arg280Leu), located at the highly conserved kinesin catalytic domain, have been reported in individuals with hereditary spastic paraplegia and Charcot-Marie-Tooth disease and are considered pathogenic (Fichera 2004, Goizet 2009, Liu 2014). Based on available information, this variant is considered to be pathogenic. References: Fichera M et al. Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. Neurology. 2004 Sep 28;63(6):1108-10. PMID: 15452312. Goizet C et al. Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. Hum Mutat. 2009 Feb;30(2):E376-85. PMID: 18853458. Liu YT et al. Extended phenotypic spectrum of KIF5A mutations: From spastic paraplegia to axonal neuropathy. Neurology. 2014 Aug 12;83(7):612-9. PMID: 25008398. Morais S et al. Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias. Eur J Hum Genet. 2017 Nov;25(11):1217-1228. Epub 2017 Aug 23. PMID: 28832565. Nam DE et al. Wide phenotypic spectrum in axonal Charcot-Marie-Tooth neuropathy type 2 patients with KIF5A mutations. Genes Genomics. 2018 Jan;40(1):77-84. PMID: 29892902.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000515919	SCV002105384	likely pathogenic	Hereditary spastic paraplegia	2017-05-23	criteria provided, single submitter	clinical testing
OMIM	RCV000030761	SCV000053422	pathogenic	Hereditary spastic paraplegia 10	2014-08-12	no assertion criteria provided	literature only