rs773138218
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_003384.3(VRK1):c.266G>A(p.Arg89Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VRK1 | NM_003384.3 | c.266G>A | p.Arg89Gln | missense_variant | 4/13 | ENST00000216639.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VRK1 | ENST00000216639.8 | c.266G>A | p.Arg89Gln | missense_variant | 4/13 | 1 | NM_003384.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251114Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135714
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461120Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 726870
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74288
ClinVar
Submissions by phenotype
Pontocerebellar hypoplasia type 1A Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 17, 2020 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 89 of the VRK1 protein (p.Arg89Gln). This variant is present in population databases (rs773138218, gnomAD 0.02%). This missense change has been observed in individuals with VRK1-related conditions (PMID: 24126608; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197213). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Oct 14, 2013 | Segregates with the phenotype in affected family - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 21, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 12, 2019 | - - |
Neuronopathy, distal hereditary motor, autosomal recessive 10 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2013 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2023 | The c.266G>A (p.R89Q) alteration is located in exon 4 (coding exon 3) of the VRK1 gene. This alteration results from a G to A substitution at nucleotide position 266, causing the arginine (R) at amino acid position 89 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (8/251114) total alleles studied. The highest observed frequency was 0.023% (8/34566) of Latino alleles. The VRK1 c.266G>A (p.R89Q) alteration has been reported in the compound heterozygous state along with another missense variant in two sisters presenting with delayed motor development, microcephaly and normal cognition. The older sister had hypotonia, progressive scoliosis, progressive muscle wasting and weakness leading to the use of a wheelchair beginning at age 4, respiratory dysfunction and limited use of her arms and hands. Her brain MRI showed a simplified gyral pattern and EMG studies showed evidence of severe axonal motor and sensory peripheral neuropathy. The younger sister had microcephaly identified in utero as well as similar brain MRI and EMG findings, but she had normal muscle bulk (Gonzaga-Jauregui, 2013). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at