Submissions for variant NM_001244008.2(KIF1A):c.5168C>T (p.Ala1723Val)

gnomAD frequency: 0.00026  dbSNP: rs199804623

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725080	SCV000333838	uncertain significance	not provided	2016-11-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000282862	SCV000429166	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	RCV000725080	SCV000574254	uncertain significance	not provided	2023-12-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26125038, 21820098, 21376300)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547693	SCV000638635	likely benign	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2024-12-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725080	SCV000885635	uncertain significance	not provided	2018-01-12	criteria provided, single submitter	clinical testing	The KIF1A c.4865C>T; p.Ala1622Val variant (rs199804623), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.04% (identified on 52 out of 126,068 chromosomes). The alanine at position 1622 is weakly conserved, considering 13 species, and computational analyses of the effects of the p.Ala1622Val variant on protein structure and function make conflicting predictions (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Ala1622Val variant cannot be determined with certainty.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848050	SCV002105263	uncertain significance	Hereditary spastic paraplegia	2021-11-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725080	SCV003814542	uncertain significance	not provided	2020-04-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725080	SCV004149649	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	KIF1A: PP2
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989518	SCV004806574	uncertain significance	Intellectual disability, autosomal dominant 9	2024-03-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021106	SCV004892297	uncertain significance	Inborn genetic diseases	2023-12-18	criteria provided, single submitter	clinical testing	The c.5168C>T (p.A1723V) alteration is located in exon 47 (coding exon 46) of the KIF1A gene. This alteration results from a C to T substitution at nucleotide position 5168, causing the alanine (A) at amino acid position 1723 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701368	SCV005204536	uncertain significance	not specified	2024-06-20	criteria provided, single submitter	clinical testing	Variant summary: KIF1A c.4865C>T (p.Ala1622Val) results in a non-conservative amino acid change located in the Pleckstrin homology domain (IPR001849) of 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 0.00028 in 248364 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in KIF1A causing NESCAV Syndrome, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4865C>T in individuals affected with NESCAV Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 282386). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000725080	SCV005409113	uncertain significance	not provided	2024-09-24	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000725080	SCV002034207	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725080	SCV002037717	likely benign	not provided		no assertion criteria provided	clinical testing