Submissions for variant NM_001244008.2(KIF1A):c.821C>T (p.Ser274Leu)

dbSNP: rs797045655

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000195049	SCV000247737	likely pathogenic	Intellectual disability, autosomal dominant 9	2015-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000236782	SCV000294165	pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate impaired microtubule binding (Boyle L et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33880452, 26125038, 21376300, 21820098)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818660	SCV000959285	pathogenic	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2023-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 274 of the KIF1A protein (p.Ser274Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant KIF1A-related conditions (PMID: 33880452; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 211298). 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 KIF1A protein function. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000236782	SCV001447692	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV001391603	SCV001451090	pathogenic	Hereditary spastic paraplegia 30		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847866	SCV002105273	likely pathogenic	Hereditary spastic paraplegia	2024-08-15	criteria provided, single submitter	clinical testing	This missense variant results in a change from serine to tryptophan at amino acid position 274. It has been previously reported in individuals with KIF1A-related disorders (PMID: 33880452). Functional studies support that this variant impairs kinesin motor activity (PMID: 33880452). This variant has not been observed in population controls of the Genome Aggregation Database (gnomAD). In silico prediction programs predict this variant to impact protein function. Based on the evidence above, this variant is classified as pathogenic (PS3, PS2, PS4_M, PM2, PM1, PP3, PP5).
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV001391603	SCV003920771	pathogenic	Hereditary spastic paraplegia 30	2023-04-27	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001391603	SCV005398446	pathogenic	Hereditary spastic paraplegia 30	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Both loss and gain of function mechanisms have been reported for variants causing spastic paraplesia (PMID: 31488895, PMID: 31455732). However neuropathy has been reported to be caused by loss of function variants only (PMID: 22258533). (N) 0104 - Dominant negative is a mechanism of disease for this gene. Missense clustering within the kinesin domain have been shown to cause NESCAV syndrome due to a dominant negative disease mechanism (PMID: 28970574). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Missense variants and variants resulting in a premature termination codon have been reported to cause dominant and recessive disease. Missense variants found within the kinesin domain are likely to cause a dominant form of disease (PMID: 31488895, PMID: 31455732, PMID: 28970574). (N) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine (exon 9). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region) (kinesin domain; PDB, NCBI). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been report once as de novo in an individual with intellectual disability, and in another individual with a KIF1A-related condition (ClinVar, LOVD). It has also been reported in a severely affected individual with a dominant condition, however the exact phenotype of this individual is unclear (Conference poster; Boyle, (2019)). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Solve-RD Consortium	RCV001391603	SCV005091537	likely pathogenic	Hereditary spastic paraplegia 30	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team