ClinVar Miner

Submissions for variant NM_003384.3(VRK1):c.1072C>T (p.Arg358Ter) (rs137853063)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000190784 SCV000244225 pathogenic Multiple congenital anomalies criteria provided, single submitter clinical testing POSITIVE: Relevant Alteration(s) Detected
Ambry Genetics RCV000210656 SCV000263027 pathogenic Inborn genetic diseases 2012-10-26 criteria provided, single submitter clinical testing
GeneDx RCV000523082 SCV000617744 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing The R358X nonsense variant in the VRK1 gene has been previously reported in the homozygous state in multiple individuals with SMA-PCH (Farwell et al., 2015; Vinograd-Byk et al., 2015). The R358X variant has also been reported in trans with the H119R variant in siblings with adult onset SMA (Stoll et al., 2116). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. 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). Therefore, we interpret R358X to be a pathogenic variant.
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.
Invitae RCV000690009 SCV000817685 pathogenic Pontocerebellar hypoplasia type 1 2018-12-31 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. This variant is present in population databases (rs137853063, ExAC 0.005%). This variant has been observed to segregate with pontocerebellar hypoplasia in a family (PMID: 19646678), and has also been observed as homozygous or in combination with another VRK1 variant in several individuals affected with spinal muscular atrophy or complex motor and sensory axonal neuropathy plus microcephaly (PMID: 24126608, 27281532). ClinVar contains an entry for this variant (Variation ID: 7497). Loss-of-function variants in VRK1 are known to be pathogenic (PMID: 19646678). For these reasons, this variant has been classified as Pathogenic.
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
OMIM RCV000007926 SCV000028131 pathogenic Pontocerebellar hypoplasia type 1A 2009-08-01 no assertion criteria provided literature only

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