ClinVar Genomic variation as it relates to human health
NM_003384.3(VRK1):c.858G>T (p.Met286Ile)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(8); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003384.3(VRK1):c.858G>T (p.Met286Ile)
Variation ID: 130730 Accession: VCV000130730.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.2 14: 96856555 (GRCh38) [ NCBI UCSC ] 14: 97322892 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 17, 2014 May 12, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003384.3:c.858G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003375.1:p.Met286Ile missense NC_000014.9:g.96856555G>T NC_000014.8:g.97322892G>T NG_016293.1:g.64209G>T - Protein change
- M286I
- Other names
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- Canonical SPDI
- NC_000014.9:96856554:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00080 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00051
Trans-Omics for Precision Medicine (TOPMed) 0.00056
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
Exome Aggregation Consortium (ExAC) 0.00070
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00080
The Genome Aggregation Database (gnomAD), exomes 0.00080
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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VRK1 | - | - |
GRCh38 GRCh37 |
535 | 562 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Mar 1, 2024 | RCV000118846.23 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Oct 24, 2022 | RCV000322092.15 | |
Uncertain significance (1) |
no assertion criteria provided
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Apr 18, 2020 | RCV000559445.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 19, 2022 | RCV002444574.9 | |
Likely benign (1) |
criteria provided, single submitter
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Aug 29, 2022 | RCV003952580.1 | |
Likely pathogenic (1) |
no assertion criteria provided
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Oct 1, 2020 | RCV002227063.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 13, 2023 | RCV003488393.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 1A
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001526889.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(Oct 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 1A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000639688.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 286 of the VRK1 protein (p.Met286Ile). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 286 of the VRK1 protein (p.Met286Ile). This variant is present in population databases (rs139476915, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VRK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 130730). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Sep 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000576977.5
First in ClinVar: May 22, 2017 Last updated: Mar 04, 2023 |
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Uncertain significance
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241074.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: VRK1 c.858G>T (p.Met286Ile) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three … (more)
Variant summary: VRK1 c.858G>T (p.Met286Ile) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 250858 control chromosomes, predominantly at a frequency of 0.0016 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.43 fold of the estimated maximal expected allele frequency for a pathogenic variant in VRK1 causing Pontocerebellar Hypoplasia, Type 1A phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.858G>T has been reported in the literature in the compound heterozygous state in two siblings affected with distal spinal muscle atrophy (Demaegd_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments; six submitters classified the variant as uncertain significance, one classified it as likely pathogenic, and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Likely benign
(Aug 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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VRK1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004776059.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(Apr 05, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000153500.1
First in ClinVar: May 17, 2014 Last updated: May 17, 2014 |
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Uncertain significance
(May 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000611066.1
First in ClinVar: May 17, 2014 Last updated: May 17, 2014 |
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 1A
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000389784.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Jan 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002679911.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.M286I variant (also known as c.858G>T), located in coding exon 9 of the VRK1 gene, results from a G to T substitution at nucleotide … (more)
The p.M286I variant (also known as c.858G>T), located in coding exon 9 of the VRK1 gene, results from a G to T substitution at nucleotide position 858. The methionine at codon 286 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004810920.2
First in ClinVar: Apr 15, 2024 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965772.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Uncertain significance
(Apr 18, 2020)
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no assertion criteria provided
Method: clinical testing
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Pontocerebellar hypoplasia type 1
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454663.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922710.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely pathogenic
(Oct 01, 2020)
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no assertion criteria provided
Method: clinical testing
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Distal spinal muscular atrophy
Affected status: no
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Accession: SCV002505665.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Number of individuals with the variant: 2
Family history: yes
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Distal spinal muscular atrophy featured by predominant calf muscle involvement in VRK1 associated disease - Case series and review. | Demaegd K | Neuromuscular disorders : NMD | 2022 | PMID: 35641352 |
Text-mined citations for rs139476915 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.