Submissions for variant NM_001244008.2(KIF1A):c.920G>A (p.Arg307Gln)

dbSNP: rs1064793161

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480291	SCV000565098	pathogenic	not provided	2021-11-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); 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: 26354034, 27034427, 28332297, 28708303, 28970574, 32737135, 34121983, 33880452, 31785789, 31805580, 21376300, 26125038, 21820098)
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	RCV000496175	SCV000586758	pathogenic	Intellectual disability, autosomal dominant 9	2017-01-06	criteria provided, single submitter	clinical testing	neurodegenerative syndrome; Intellectual disability; hypotonia; cerebellar atrophy; optic nerve atrophy; congenital retinal dystrophy; pyramidal syndrome (Rossolimo and Babinsky signs)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705000	SCV000833977	pathogenic	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2021-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 307 of the KIF1A protein (p.Arg307Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with KIF1A-related conditions (PMID: 26354034, 27034427, 28708303). In at least one individual the variant was observed to be de novo. This variant is also known as c.902G>A. ClinVar contains an entry for this variant (Variation ID: 418275). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000496175	SCV001164442	likely pathogenic	Intellectual disability, autosomal dominant 9	2018-12-03	criteria provided, single submitter	research	The heterozyous p.Arg307Gln variant in KIF1A was identified by our study in one individual with GLUT1 deficiency syndrome. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies and is predicted to shorten the length of the protein by three residues due to an in-frame deletion. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu209_Pro211del variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS2, PM4, PP3 (Richards 2015).
SIB Swiss Institute of Bioinformatics	RCV000496175	SCV001426722	likely pathogenic	Intellectual disability, autosomal dominant 9	2020-06-15	criteria provided, single submitter	curation	This variant is interpreted as likely pathogenic for NESCAV syndrome, 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); 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); De novo (paternity and maternity confirmed) (PS2).
Neuberg Centre For Genomic Medicine, NCGM	RCV000496175	SCV004047769	pathogenic	Intellectual disability, autosomal dominant 9		criteria provided, single submitter	clinical testing	The c.920G>A (p.Arg307Gln) missense variant in KIF1A gene has been reported in individuals affected with intellectual disability, cerebellar atrophy, spasticity and optic atrophy (Hotchkiss et al., 2016; Ohba et al., 2015), and an individual with neurodevelopmental disorder (Chérot et al., 2018). The p.Arg307Gln variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/Likely Pathogenic. The amino acid Arg at position 307 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg307Gln in KIF1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004529605	SCV004108521	pathogenic	KIF1A-related disorder	2022-09-12	criteria provided, single submitter	clinical testing	The KIF1A c.920G>A variant is predicted to result in the amino acid substitution p.Arg307Gln. This variant, also referred to as c.902G>A, has been documented as de novo in multiple patients with spastic paraplegia, optic neve atrophy, brain anomalies, peripheral neuropathy, cognitive and language impairment, and motor delays (Hotchkiss et al. 2016. PubMed ID: 27034427; Patient 3 Ohba et al. 2015. PubMed ID: 26354034; Patients 8 and 9 in Nicita et al. 2020. PubMed ID: 32737135 ) and in a patient from a neurodevelopmental disorder cohort (Patient 18, Chérot et al. 2017. PubMed ID: 28708303). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted by multiple laboratories in ClinVar as pathogenic and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/418275). In addition, other variants impacting the same amino acid residue (p.Arg307Gly and p.Arg307Pro) have also been reported in a patient with cerebellar ataxia (Patient 041 in Sun et al. 2019. PubMed ID: 29915382) and in twins with brain anomalies, epilepsy, and neuropathy (Patient 5A and 5B in Nemani et al. 2020. PubMed ID: 32096284). Based on this evidence, the c.920G>A (p.Arg307Gln) variant is interpreted as pathogenic.
Solve-RD Consortium	RCV004767290	SCV005091538	likely pathogenic	Hereditary spastic paraplegia 30	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team