ClinVar Miner

Submissions for variant NM_003384.3(VRK1):c.1072C>T (p.Arg358Ter)

gnomAD frequency: 0.00006  dbSNP: rs137853063
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000007926 SCV000256754 pathogenic Pontocerebellar hypoplasia type 1A 2013-10-14 criteria provided, single submitter research Segregates with the phenotype in affected family
Ambry Genetics RCV000210656 SCV000263027 pathogenic Inborn genetic diseases 2023-01-10 criteria provided, single submitter clinical testing 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.
GeneDx RCV000523082 SCV000617744 pathogenic not provided 2022-02-24 criteria provided, single submitter clinical testing 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)
Labcorp Genetics (formerly Invitae), Labcorp RCV000007926 SCV000817685 pathogenic Pontocerebellar hypoplasia type 1A 2024-01-22 criteria provided, single submitter clinical testing 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.
Kariminejad - Najmabadi Pathology & Genetics Center RCV001836703 SCV000999244 pathogenic Abnormality of the musculature 2021-07-10 criteria provided, single submitter clinical testing
Genetics Institute, Tel Aviv Sourasky Medical Center RCV000007926 SCV001593199 pathogenic Pontocerebellar hypoplasia type 1A 2021-05-12 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000523082 SCV002020880 pathogenic not provided 2021-08-16 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000007926 SCV002813240 pathogenic Pontocerebellar hypoplasia type 1A 2021-09-06 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000007926 SCV003761341 pathogenic Pontocerebellar hypoplasia type 1A 2023-01-25 criteria provided, single submitter curation 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).
OMIM RCV000007926 SCV000028131 pathogenic Pontocerebellar hypoplasia type 1A 2013-12-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000007926 SCV000840345 not provided Pontocerebellar hypoplasia type 1A no assertion provided phenotyping only 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.
Natera, Inc. RCV000690009 SCV001456102 pathogenic Congenital pontocerebellar hypoplasia type 1 2020-09-16 no assertion criteria provided clinical testing
OMIM RCV003387437 SCV004098882 pathogenic Neuronopathy, distal hereditary motor, autosomal recessive 10 2013-12-01 no assertion criteria provided literature only

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