2-240775889-C-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001244008.2(KIF1A):c.920G>A(p.Arg307Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R307G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001244008.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460308Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 726556
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 9 Pathogenic:5
neurodegenerative syndrome; Intellectual disability; hypotonia; cerebellar atrophy; optic nerve atrophy; congenital retinal dystrophy; pyramidal syndrome (Rossolimo and Babinsky signs) -
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). -
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). -
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. -
The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 31488895). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.93 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.94 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000418275 /PMID: 26354034 /3billion dataset). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26354034). Different missense changes at the same codon (p.Arg307Gly, p.Arg307Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000435636, VCV000869126 /PMID: 29915382, 32096284). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:1
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) -
Hereditary spastic paraplegia 30 Pathogenic:1
Variant confirmed as disease-causing by referring clinical team -
KIF1A-related disorder Pathogenic:1
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. -
Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at