chr2-240783791-A-G
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001244008.2(KIF1A):c.746T>C(p.Leu249Pro) 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. L249Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001244008.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF1A | NM_001244008.2 | c.746T>C | p.Leu249Pro | missense_variant | 8/49 | ENST00000498729.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF1A | ENST00000498729.9 | c.746T>C | p.Leu249Pro | missense_variant | 8/49 | 5 | NM_001244008.2 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 29, 2019 | - - |
Intellectual disability, autosomal dominant 9 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 21, 2020 | The p.Leu249Pro variant in KIF1A has been reported as de novo through trio WES in an individual with features associated with KIF1A-related neurological disorder (KAND), such as severe developmental delay, cerebellar ataxia and atrophy on MRI, spastic paraparesis, and eye findings. The individual also carried a de novo duplication of 22q11.23 that is known to demonstrate variable expression and incomplete penetrance (Demily 2018, PMID: 29589274). The p.Leu249Pro variant was also confirmed to be de novo through trio whole genome sequencing in a young woman with developmental delay, seizures, hypotonia, intellectual disability, cerebellar atrophy, and cortical visual impairment by the Broad Institute Rare Genomes Project. It was absent from large population studies. Another variant involving this codon (p.Leu249Gln) has been identified in other individuals with KIF1A-related neurological disorder (ClinVar variation ID 162061) suggesting that changes at this codon are not tolerated. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in this region of the KIF1A gene in the general population is lower than expected, suggesting that a missense variant in this region may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant KIF1A-related neurological disorder. ACMG/AMP Criteria applied: PS2, PM2_Supporting, PM5_Supporting, PP2, PP3 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2022 | Not observed at significant frequency 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: 26125038, 21820098, 21376300, 29589274) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at