Submissions for variant NM_001244008.2(KIF1A):c.32G>A (p.Arg11Gln)

dbSNP: rs1575654528

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810861	SCV000951098	pathogenic	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2022-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 11 of the KIF1A protein (p.Arg11Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant KIF1A-related conditions (PMID: 32096284; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 654820). This variant disrupts the p.Arg11 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28832565). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KIF1A protein function. For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics	RCV001251221	SCV001426712	likely pathogenic	Hereditary spastic paraplegia 30	2020-06-15	criteria provided, single submitter	curation	This variant is interpreted as likely pathogenic for spastic paraplegia 30, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2).
Paris Brain Institute, Inserm - ICM	RCV001251221	SCV001451071	pathogenic	Hereditary spastic paraplegia 30		criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001251221	SCV001519152	pathogenic	Hereditary spastic paraplegia 30	2021-01-04	criteria provided, single submitter	research
Baylor Genetics	RCV001332405	SCV001524727	likely pathogenic	Intellectual disability, autosomal dominant 9	2020-07-22	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001332405	SCV002041667	likely pathogenic	Intellectual disability, autosomal dominant 9	2021-11-11	criteria provided, single submitter	clinical testing	Variant summary: KIF1A c.32G>A (p.Arg11Gln) results in a conservative amino acid change located in the Kinesin motor domain (IPR001752) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. A different amino acid change at the same location, c.31C>T (p.Arg11Trp) has been reported in settings of spastic paraplegia in the HGMD database supporting the functional relevance of this residue to overall protein function. The variant was absent in 244322 control chromosomes. c.32G>A has been reported in the literature as a de-novo variant in at-least one individual with a developmental disorder and as an unknown inheritance in two individuals with features of KIF1A-related disorders/KIF1A-related neurological disorder (Turner_2019, Nemani_2020, Boyle_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV003106073	SCV003762069	pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35163618, 34487232, Anazawa2022[Preprint], 26125038, 21820098, 21376300, 33880452, 34445196, 31785789, 32096284)
Genomics England Pilot Project, Genomics England	RCV001251221	SCV001760078	likely pathogenic	Hereditary spastic paraplegia 30		no assertion criteria provided	clinical testing