Submissions for variant NM_004984.4(KIF5A):c.838C>T (p.Arg280Cys)

dbSNP: rs121434442

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000993045	SCV001145747	likely pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing	This variant appears to segregate with spastic paraplegia in at least one family. Functional studies showed that mutant proteins have reduced microtubule affinity but still possess the regulatory mechanisms (PMID: 18203753). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
CeGaT Center for Human Genetics Tuebingen	RCV000993045	SCV001250238	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000007209	SCV001451233	pathogenic	Hereditary spastic paraplegia 10		criteria provided, single submitter	clinical testing
Invitae	RCV001387529	SCV001588190	pathogenic	Spastic paraplegia	2022-12-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 18853458, 25008398, 28832565, 29892902). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KIF5A function (PMID: 18203753). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 6807). This missense change has been observed in individuals with KIF5A-related conditions (PMID: 15452312, 25008398, 31211173; Invitae). 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 cysteine, which is neutral and slightly polar, at codon 280 of the KIF5A protein (p.Arg280Cys).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000993045	SCV001762183	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847593	SCV002105383	pathogenic	Hereditary spastic paraplegia	2016-12-12	criteria provided, single submitter	clinical testing
OMIM	RCV000007209	SCV000027405	pathogenic	Hereditary spastic paraplegia 10	2014-08-12	no assertion criteria provided	literature only