ClinVar Miner

Submissions for variant NM_003384.3(VRK1):c.961C>T (p.Arg321Cys) (rs772731615)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000191144 SCV000245553 likely pathogenic Pontocerebellar hypoplasia type 1A 2014-01-27 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it once in our laboratory in trans with another missense variant [H119R] in a 33-year-old male with clinical diagnoses of distal spinal muscular atrophy and motor neuropathy. Variant likely pathogenic in recessive state; heterozygotes would be carriers.
Counsyl RCV000191144 SCV000800730 uncertain significance Pontocerebellar hypoplasia type 1A 2017-08-03 criteria provided, single submitter clinical testing
GeneDx RCV000435348 SCV000535254 uncertain significance not specified 2017-10-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the VRK1 gene. The R321C variant was found in trans with the H119R variant in an individual with early onset amyotrophic lateral sclerosis (Nguyen et al., 2015). The R321C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R321C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000692666 SCV000820501 uncertain significance Pontocerebellar hypoplasia type 1 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 321 of the VRK1 protein (p.Arg321Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs772731615, ExAC 0.1%). This variant has been reported as in combination with other VRK1 variants in an individual affected with amyotrophic lateral sclerosis (PMID: 26583493) and in individuals affected with VRK1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 209205). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.

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