ClinVar Miner

Submissions for variant NM_003384.3(VRK1):c.706G>A (p.Val236Met)

dbSNP: rs771364038
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Total submissions: 7
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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 RCV000203265 SCV000256752 pathogenic Pontocerebellar hypoplasia type 1A 2013-10-14 criteria provided, single submitter research Segregates with the phenotype in affected family
GeneDx RCV003441782 SCV000617743 pathogenic not provided 2024-03-27 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, as the V236M variant results in loss of kinase activity (PMID: 31527692); Reported in trans with another VRK1 variant in two siblings with microcephaly and severe, rapidly progressive distal symmetric polyneuropathy with normal intellect in published literature (PMID: 24126608); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 24970098, 27281532, 25609612, 26583493, 34169149, 30617279, 30847374, 31178479, 27149842, 35641352, 31560180, 31090908, 24126608, 31527692)
Labcorp Genetics (formerly Invitae), Labcorp RCV000203265 SCV000836197 pathogenic Pontocerebellar hypoplasia type 1A 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 236 of the VRK1 protein (p.Val236Met). This variant is present in population databases (rs771364038, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of distal hereditary motor neuropathy (PMID: 24126608; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218924). 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. Experimental studies have shown that this missense change affects VRK1 function (PMID: 31527692). For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company RCV000203265 SCV002059512 likely pathogenic Pontocerebellar hypoplasia type 1A 2020-07-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV002517363 SCV003566935 uncertain significance Inborn genetic diseases 2021-12-16 criteria provided, single submitter clinical testing The c.706G>A (p.V236M) alteration is located in exon 8 (coding exon 7) of the VRK1 gene. This alteration results from a G to A substitution at nucleotide position 706, causing the valine (V) at amino acid position 236 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV000203265 SCV002093696 uncertain significance Pontocerebellar hypoplasia type 1A 2021-02-15 no assertion criteria provided clinical testing
OMIM RCV003387514 SCV004098884 pathogenic Neuronopathy, distal hereditary motor, autosomal recessive 10 2013-12-01 no assertion criteria provided literature only

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