ClinVar Genomic variation as it relates to human health
NM_003384.3(VRK1):c.1072C>T (p.Arg358Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003384.3(VRK1):c.1072C>T (p.Arg358Ter)
Variation ID: 7497 Accession: VCV000007497.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.2 14: 96876033 (GRCh38) [ NCBI UCSC ] 14: 97342370 (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 Apr 4, 2013 May 1, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003384.3:c.1072C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003375.1:p.Arg358Ter nonsense NC_000014.9:g.96876033C>T NC_000014.8:g.97342370C>T NG_016293.1:g.83687C>T - Protein change
- R358*
- Other names
- NM_003384.3(VRK1):c.1072C>T
- p.Arg358Ter
- Canonical SPDI
- NC_000014.9:96876032:C: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
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
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000007926.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 10, 2023 | RCV000210656.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 24, 2022 | RCV000523082.8 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV000690009.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001836703.2 | |
Pathogenic (1) |
no assertion criteria provided
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Dec 1, 2013 | RCV003387437.1 |
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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Pathogenic
(May 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 1A
fetal CNS anomalies
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
inherited
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Genetics Institute, Tel Aviv Sourasky Medical Center
Accession: SCV001593199.1
First in ClinVar: May 14, 2021 Last updated: May 14, 2021 |
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the musculature
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV000999244.2
First in ClinVar: Nov 29, 2019 Last updated: Feb 20, 2022 |
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Pathogenic
(Aug 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002020880.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 22, 2024)
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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: SCV000817685.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg358*) in the VRK1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg358*) in the VRK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VRK1 are known to be pathogenic (PMID: 19646678, 24126608, 27281532). This variant is present in population databases (rs137853063, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with pontocerebellar hypoplasia, spinal muscular atrophy or complex motor, and sensory axonal neuropathy plus microcephaly (PMID: 19646678, 24126608, 27281532). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7497). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 14, 2013)
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criteria provided, single submitter
Method: research
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Pontocerebellar hypoplasia type 1A
(Autosomal recessive inheritance)
Affected status: no, yes
Allele origin:
germline
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000256754.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
Segregates with the phenotype in affected family
Observation 1:
Number of individuals with the variant: 1
Family history: no
Observation 2:
Number of individuals with the variant: 3
Family history: no
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Pathogenic
(Sep 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 1A
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813240.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: curation
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Pontocerebellar hypoplasia type 1A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761341.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The homozygous p.Arg358Ter variant in VRK1 was identified by our study in two siblings with pontocerebellar hypoplasia. The p.Arg358Ter variant in VRK1 has been previously … (more)
The homozygous p.Arg358Ter variant in VRK1 was identified by our study in two siblings with pontocerebellar hypoplasia. The p.Arg358Ter variant in VRK1 has been previously reported in 5 unrelated individuals with pontocerebellar hypoplasia type IA (PMID: 25356970, PMID: 30108342, PMID: 24126608, PMID: 19646678, PMID: 27281532), and segregated with disease in 2 affected relatives from one family (PMID: 27281532), but has been identified in 0.004% (3/67996) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137853063). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 5 unrelated affected individuals, 4 were homozygotes (PMID: 25356970, PMID: 30108342, PMID: 24126608, PMID: 19646678) and 1 was a compound heterozygote who carried a pathogenic variant in trans (PMID: 27281532, ClinVar Variation ID: 209204), which increases the likelihood that the p.Arg358Ter variant in VRK1 is pathogenic. This variant has also been reported in ClinVar (Variation ID: 7497) and has been interpreted as pathogenic by multiple submitters. In vitro functional studies provide some evidence that the p.Arg358Ter variant may impact protein function (PMID: 25609612, PMID: 21920476, PMID: 31527692). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 358, which is predicted to lead to a truncated or absent protein. Loss of function of the VRK1 gene is an established disease mechanism in autosomal recessive pontocerebellar hypoplasia type IA. In summary, this variant meets criteria to be classified as pathogenic for pontocerebellar hypoplasia type IA. ACMG/AMP Criteria applied: PVS1, PS3_Supporting, PM2_Supporting, PM3_Strong, PP1_Moderate (Richards 2015). (less)
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Pathogenic
(Feb 24, 2022)
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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: SCV000617744.5
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies in lymphoblastoid cell lines demonstrate an extreme reduction in the mRNA and protein levels of APP (amyloid-beta precursor protein), which has a … (more)
Published functional studies in lymphoblastoid cell lines demonstrate an extreme reduction in the mRNA and protein levels of APP (amyloid-beta precursor protein), which has a role in neuronal migration (Vinograd-Byk et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21920476, 25525159, 19646678, 25609612, 25356970, 27281532, 24126608, 30108342, 31527692, 30617279, 31589614, 21749694) (less)
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Pathogenic
(Jan 10, 2023)
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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: SCV000263027.6
First in ClinVar: Apr 08, 2016 Last updated: May 01, 2024 |
Comment:
The c.1072C>T (p.R358*) alteration, located in exon 12 (coding exon 11) of the VRK1 gene, consists of a C to T substitution at nucleotide position … (more)
The c.1072C>T (p.R358*) alteration, located in exon 12 (coding exon 11) of the VRK1 gene, consists of a C to T substitution at nucleotide position 1072. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 358. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (16/250524) total alleles studied. The highest observed frequency was 0.149% (15/10058) of Ashkenazi Jewish alleles. This alteration has been detected in the homozygous state and in trans with another VRK1 disease-causing mutation in multiple unrelated individuals with VRK1-related motor and sensory neuropathy with or without pontocerebellar hypoplasia (Renbaum, 2009; Farwell, 2015; Stoll, 2016; Gonzaga-Jauregui, 2013; Reches, 2018; Ambry internal data). Functional studies suggest that this alteration demonstrates mislocalization, reduced protein stability and reduced kinase activity (Martin-Doncel, 2019; Sanz-Garcia, 2011). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Dec 01, 2013)
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no assertion criteria provided
Method: literature only
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PONTOCEREBELLAR HYPOPLASIA, TYPE 1A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028131.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 28, 2023 |
Comment on evidence:
Pontocerebellar Hypoplasia Type 1A In an Ashkenazi Jewish girl, born of consanguineous parents, with pontocerebellar hypoplasia type 1A (PCH1A; 607596), Renbaum et al. (2009) identified … (more)
Pontocerebellar Hypoplasia Type 1A In an Ashkenazi Jewish girl, born of consanguineous parents, with pontocerebellar hypoplasia type 1A (PCH1A; 607596), Renbaum et al. (2009) identified a homozygous c.1072C-T transition in exon 12 of the VRK1 gene, resulting in an arg358-to-ter (R358X) substitution within the NLS. There were 3 affected family members, all of whom died by age 12 years. Clinical features included poor sucking, developmental delay, progressive muscle weakness, ataxia, hyperreflexia, foot deformities, and cerebellar hypoplasia. Skeletal muscle biopsy showed neurogenic atrophy. The mutation was detected in heterozygosity in 2 of 449 unaffected Ashkenazi Jewish individuals. Autosomal Recessive Distal Hereditary Motor Neuronopathy 10 In a 9-year-old boy (patient BAB5311), born of unrelated Ashkenazi Jewish parents, with autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10; 620542), Gonzaga-Jauregui et al. (2013) identified a homozygous c.1072C-T transition (c.1072C-T, NM_003384) in the VRK1 gene resulting in an R358X mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation has a frequency of 0.007% in the general population and 0.0116% in the population of European descent. Haplotype analysis confirmed a founder effect for this mutation in the Ashkenazi Jewish population. Functional studies of the variant and studies of patient cells were not performed. The patient showed decreased fetal movements and microcephaly in utero. He had hypotonia, scoliosis, poor feeding requiring tube-feeding, and electrophysiologic evidence of an axonal sensorimotor neuropathy. He did not have ataxia, hypertonia, impaired intellectual development, or pontocerebellar hypoplasia on brain imaging. Brain imaging showed a normal pons and cerebellar hemispheres, but an underdeveloped cerebellar vermis. It also showed simplified gyral pattern and progressive volume loss. Gonzaga-Jauregui et al. (2013) noted that although there were some overlapping features, the phenotype in this patient was distinct from the PCH1A phenotype reported by Renbaum et al. (2009). (less)
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Pathogenic
(Dec 01, 2013)
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no assertion criteria provided
Method: literature only
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 10
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV004098882.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment on evidence:
Pontocerebellar Hypoplasia Type 1A In an Ashkenazi Jewish girl, born of consanguineous parents, with pontocerebellar hypoplasia type 1A (PCH1A; 607596), Renbaum et al. (2009) identified … (more)
Pontocerebellar Hypoplasia Type 1A In an Ashkenazi Jewish girl, born of consanguineous parents, with pontocerebellar hypoplasia type 1A (PCH1A; 607596), Renbaum et al. (2009) identified a homozygous c.1072C-T transition in exon 12 of the VRK1 gene, resulting in an arg358-to-ter (R358X) substitution within the NLS. There were 3 affected family members, all of whom died by age 12 years. Clinical features included poor sucking, developmental delay, progressive muscle weakness, ataxia, hyperreflexia, foot deformities, and cerebellar hypoplasia. Skeletal muscle biopsy showed neurogenic atrophy. The mutation was detected in heterozygosity in 2 of 449 unaffected Ashkenazi Jewish individuals. Autosomal Recessive Distal Hereditary Motor Neuronopathy 10 In a 9-year-old boy (patient BAB5311), born of unrelated Ashkenazi Jewish parents, with autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10; 620542), Gonzaga-Jauregui et al. (2013) identified a homozygous c.1072C-T transition (c.1072C-T, NM_003384) in the VRK1 gene resulting in an R358X mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation has a frequency of 0.007% in the general population and 0.0116% in the population of European descent. Haplotype analysis confirmed a founder effect for this mutation in the Ashkenazi Jewish population. Functional studies of the variant and studies of patient cells were not performed. The patient showed decreased fetal movements and microcephaly in utero. He had hypotonia, scoliosis, poor feeding requiring tube-feeding, and electrophysiologic evidence of an axonal sensorimotor neuropathy. He did not have ataxia, hypertonia, impaired intellectual development, or pontocerebellar hypoplasia on brain imaging. Brain imaging showed a normal pons and cerebellar hemispheres, but an underdeveloped cerebellar vermis. It also showed simplified gyral pattern and progressive volume loss. Gonzaga-Jauregui et al. (2013) noted that although there were some overlapping features, the phenotype in this patient was distinct from the PCH1A phenotype reported by Renbaum et al. (2009). (less)
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Pathogenic
(Sep 16, 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: SCV001456102.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Pontocerebellar hypoplasia type 1A
Affected status: yes
Allele origin:
germline
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GenomeConnect, ClinGen
Accession: SCV000840345.1
First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Premature birth (present) , Abnormal delivery (present) , Failure to thrive (present) , Abnormality of the skull (present) , Abnormality of eye movement (present) , … (more)
Premature birth (present) , Abnormal delivery (present) , Failure to thrive (present) , Abnormality of the skull (present) , Abnormality of eye movement (present) , Abnormality of movement (present) , Generalized hypotonia (present) , Hypertonia (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Short attention span (present) , Depressivity (present) , Anxiety (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the limbs (present) , EMG abnormality (present) , Abnormality of muscle physiology (present) , Restrictive ventilatory defect (present) , Respiratory insufficiency (present) , Decreased pulmonary function (present) , Abnormality of the lung (present) , Feeding difficulties (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Testing laboratory: Ambry Genetics
Date variant was reported to submitter: 2012-06-29
Testing laboratory interpretation: Pathogenic
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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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VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes. | Martín-Doncel E | Scientific reports | 2019 | PMID: 31527692 |
Whole-exome sequencing in fetuses with central nervous system abnormalities. | Reches A | Journal of perinatology : official journal of the California Perinatal Association | 2018 | PMID: 30108342 |
Novel motor phenotypes in patients with VRK1 mutations without pontocerebellar hypoplasia. | Stoll M | Neurology | 2016 | PMID: 27281532 |
Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. | Farwell KD | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25356970 |
Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly. | Gonzaga-Jauregui C | JAMA neurology | 2013 | PMID: 24126608 |
Substrate profiling of human vaccinia-related kinases identifies coilin, a Cajal body nuclear protein, as a phosphorylation target with neurological implications. | Sanz-García M | Journal of proteomics | 2011 | PMID: 21920476 |
Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. | Renbaum P | American journal of human genetics | 2009 | PMID: 19646678 |
Text-mined citations for rs137853063 ...
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.