Submissions for variant NM_001244008.2(KIF1A):c.3668C>T (p.Thr1223Met)

gnomAD frequency: 0.00021  dbSNP: rs374873057

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190656	SCV000244096	uncertain significance	Inborn genetic diseases	2019-09-29	criteria provided, single submitter	clinical testing	The p.T1122M variant (also known as c.3365C>T), located in coding exon 32 of the KIF1A gene, results from a C to T substitution at nucleotide position 3365. The threonine at codon 1122 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000311119	SCV000429235	uncertain significance	Spastic Paraplegia, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000356396	SCV000429236	uncertain significance	Hereditary sensory and autonomic neuropathy type 2	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000401309	SCV000429237	uncertain significance	Intellectual Disability, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000504400	SCV000595401	uncertain significance	not specified	2016-08-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639825	SCV000761406	likely benign	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001545198	SCV001764479	uncertain significance	not provided	2024-10-01	criteria provided, single submitter	clinical testing	Reported previously, using alternate nomenclature, in a patient with HSP; however, no further clinical or segregation information was provided (PMID: 29691679); 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: 29691679)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847846	SCV002104864	uncertain significance	Hereditary spastic paraplegia	2020-05-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001545198	SCV002770539	uncertain significance	not provided	2022-03-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504400	SCV004028880	uncertain significance	not specified	2023-07-06	criteria provided, single submitter	clinical testing	Variant summary: KIF1A c.3365C>T (p.Thr1122Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 205930 control chromosomes in the gnomAD database, including 1 homozygotes. c.3365C>T has been reported in the literature in an individual affected with Hereditary Spastic Paraplegia and the variant was inherited from an asymptomatic parent (example: Travaglini_2018). This report does not provide unequivocal conclusions about association of the variant with NESCAV Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29691679). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=1) and VUS (n=7). Based on the evidence outlined above, the variant was classified as uncertain significance.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252530	SCV001428287	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing