ClinVar Miner

Submissions for variant NM_003384.3(VRK1):c.683C>T (p.Thr228Met)

gnomAD frequency: 0.00004  dbSNP: rs146113610
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001830759 SCV000946944 uncertain significance Pontocerebellar hypoplasia type 1A 2022-03-11 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 228 of the VRK1 protein (p.Thr228Met). This variant is present in population databases (rs146113610, gnomAD 0.009%). This missense change has been observed in individual(s) with VRK1-related conditions (PMID: 31090908). ClinVar contains an entry for this variant (Variation ID: 651537). 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 disruptive. 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.
Molecular Oncology Research Center, Barretos Cancer Hospital RCV001374508 SCV001438601 likely pathogenic Hereditary breast ovarian cancer syndrome 2020-08-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226397 SCV003922897 uncertain significance not specified 2023-03-10 criteria provided, single submitter clinical testing Variant summary: VRK1 c.683C>T (p.Thr228Met) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251366 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in VRK1 causing Pontocerebellar Hypoplasia, Type 1A (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.683C>T has been reported in the literature in an individual affected with a slowly progressive distal motor neuropathy (El-Bazzal_2019). This report does not provide unequivocal conclusions about association of the variant with Pontocerebellar Hypoplasia, Type 1A. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001830759 SCV002093695 uncertain significance Pontocerebellar hypoplasia type 1A 2020-02-12 no assertion criteria provided clinical testing

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