Submissions for variant NM_001244008.2(KIF1A):c.2680G>A (p.Asp894Asn)

gnomAD frequency: 0.00002  dbSNP: rs1064796756

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480827	SCV000573800	uncertain significance	not provided	2021-06-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31130284, 27535533, 26410750, 21376300)
Baylor Genetics	RCV001333026	SCV001525507	uncertain significance	Hereditary spastic paraplegia 30	2020-02-28	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002431417	SCV002742194	uncertain significance	Inborn genetic diseases	2019-09-20	criteria provided, single submitter	clinical testing	The p.D894N variant (also known as c.2680G>A), located in coding exon 26 of the KIF1A gene, results from a G to A substitution at nucleotide position 2680. The aspartic acid at codon 894 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is 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.
Athena Diagnostics	RCV000480827	SCV002770537	uncertain significance	not provided	2021-10-25	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787792	SCV005399208	likely benign	Intellectual disability, autosomal dominant 9	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely Benign. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Missense clustering within the kinesin domain with a dominant negative effect have been shown to cause NESCAV syndrome (PMID: 28970574). Both loss and gain of function mechanisms have been reported for variants causing spastic paraplesia (PMID 31488895, PMID: 31455732), however neuropathy has only been reported to be caused by loss of function mutations (PMID: 22258533). (I) 0108 - This gene is associated with both recessive and dominant disease. Both truncating and missense variants have been reported to each 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). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0219 - This variant is non-coding in an alternative transcript. The variant is intronic in all other transcripts (NCBI, UCSC). (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of KIF1A-related intellectual disability (gnomAD v2: 5 heterozygotes, 0 homozygotes). (SB) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. The variant has previously been classified as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV004737554	SCV005359117	uncertain significance	KIF1A-related disorder	2024-07-15	no assertion criteria provided	clinical testing	The KIF1A c.2680G>A variant is predicted to result in the amino acid substitution p.Asp894Asn. This variant was reported in the heterozygous state in an individual that presented with failure to thrive, growth retardation, facial dysmorphism, congenital dislocation of the hip, microcephaly, muscle weakness, spasticity (Table S1, Monies et al. 2019. PubMed ID: 31130284). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.