2-240775889-C-T

Position:

• chr2-240775889-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.71

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1A. . Gene score misZ 5.1579 (greater than the threshold 3.09). Trascript score misZ 5.0191 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 2-240775889-C-T is Pathogenic according to our data. Variant chr2-240775889-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240775889-C-T is described in Lovd as [Pathogenic]. Variant chr2-240775889-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.920G>A	p.Arg307Gln	missense_variant	11/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.920G>A	p.Arg307Gln	missense_variant	11/49	5	NM_001244008.2	ENSP00000438388

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460308 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726556

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jun 15, 2020	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). -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	Jan 06, 2017	neurodegenerative syndrome; Intellectual disability; hypotonia; cerebellar atrophy; optic nerve atrophy; congenital retinal dystrophy; pyramidal syndrome (Rossolimo and Babinsky signs) -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -

Hereditary spastic paraplegia 30 Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2021

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) -

KIF1A-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2021

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 418275). This variant is also known as c.902G>A. 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 not present in population databases (ExAC no frequency). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;.;.;.;.;.;H;.;.;.;.;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	.;D;D;.;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	.;D;D;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.;.;.;D;.
Vest4		0.98, 0.98
MutPred		0.93		Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);.;Loss of MoRF binding (P = 0.0405);Loss of MoRF binding (P = 0.0405);
MVP		0.95
MPC		2.6
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.88
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064793161; hg19: chr2-241715306;