Submissions for variant NM_001244008.2(KIF1A):c.4889G>A (p.Arg1630Gln)

gnomAD frequency: 0.00228  dbSNP: rs191428830

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000360457	SCV000429179	uncertain significance	Hereditary spastic paraplegia 30	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000413251	SCV000491944	uncertain significance	not specified	2016-11-17	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the KIF1A gene. The R1529Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1529Q variant was not observed with any significant frequency in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project but the 1000 Genomes Project reports R1529Q was observed in 8/198 (4.0%) alleles from individuals of Finnish background, indicating it may be a rare (benign) variant in this population. The R1529Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, this amino acid substitution does not occur within the predicted motor domain of the protein, where all pathogenic missense KIF1A pathogenic variants have been identified to-date (Lee et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082704	SCV000638625	benign	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2024-01-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712151	SCV000842575	likely benign	not provided	2017-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002338933	SCV002638589	benign	Inborn genetic diseases	2018-11-08	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000712151	SCV004562343	benign	not provided	2023-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544626	SCV004764888	benign	KIF1A-related disorder	2021-07-12	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).