Submissions for variant NM_001244008.2(KIF1A):c.4771C>T (p.Arg1591Trp)

gnomAD frequency: 0.00016  dbSNP: rs201139273

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000437823	SCV000511570	uncertain significance	not provided	2017-01-05	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544072	SCV000638623	likely benign	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2024-01-09	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000437823	SCV000706880	uncertain significance	not provided	2017-03-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000437823	SCV001802574	uncertain significance	not provided	2023-11-22	criteria provided, single submitter	clinical testing	Observed with another variant on the opposite allele (in trans) in a patient with seizures, optic nerve atrophy, and hypotonia; however, spasticity and neuropathy were not reported (PMID: 33880452); 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: 33880452)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848743	SCV002105248	uncertain significance	Hereditary spastic paraplegia	2021-04-22	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000544072	SCV002564161	uncertain significance	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2021-09-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002338983	SCV002635705	uncertain significance	Inborn genetic diseases	2022-03-21	criteria provided, single submitter	clinical testing	The p.R1591W variant (also known as c.4771C>T), located in coding exon 44 of the KIF1A gene, results from a C to T substitution at nucleotide position 4771. The arginine at codon 1591 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000437823	SCV004042130	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	KIF1A: PM2
Clinical Genetics, Academic Medical Center	RCV000437823	SCV001922403	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000437823	SCV001973518	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544732	SCV004767626	uncertain significance	KIF1A-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The KIF1A c.4771C>T variant is predicted to result in the amino acid substitution p.Arg1591Trp. This variant was reported in the compound heterozygous state in a patient with seizures, optic nerve atrophy and hypotonia (Patient K_011 in Table S1, Boyle et al. 2021. PubMed ID: 33880452). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.043% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations in ClinVar ranging from uncertain to likely benign (review.ncbi.nlm.nih.gov/clinvar/variation/377242/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.