Submissions for variant NM_004984.4(KIF5A):c.610C>T (p.Arg204Trp)

dbSNP: rs1555177629

Total submissions: 7

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	RCV000516107	SCV000574451	pathogenic	Hereditary spastic paraplegia	2017-03-07	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801216	SCV000940983	pathogenic	Spastic paraplegia	2022-03-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg204 amino acid residue in KIF5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18853458, 21623771, 25008398, 26543653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 424651). This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia and axonal sensorimotor polyneuropathy (CMT2) (PMID: 18500496, 25008398, 28832565). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 204 of the KIF5A protein (p.Arg204Trp).
Paris Brain Institute, Inserm - ICM	RCV001391456	SCV001451225	pathogenic	Hereditary spastic paraplegia 10		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000516107	SCV002105381	likely pathogenic	Hereditary spastic paraplegia	2016-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV002222527	SCV002499799	pathogenic	not provided	2021-10-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect by showing significantly reduced catalytic and mechanical activities of KIF5A protein expressing the variant p.R204W (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: 33059505, 25008398, 30057544, 26543653, 29892902, 28832565, 31422367, 18853458, 22785106, 28678816, 21623771, Mahase2020[Computational], 18500496)
CeGaT Center for Human Genetics Tuebingen	RCV002222527	SCV002545041	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	KIF5A: PM1, PM2, PP1:Moderate, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting
Athena Diagnostics	RCV002222527	SCV004229162	pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with autosomal dominant spastic paraplegia. This variant associates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).