ClinVar Miner

Submissions for variant NM_003384.3(VRK1):c.901A>G (p.Lys301Glu) (rs149661915)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000765200 SCV000389786 uncertain significance Pontocerebellar hypoplasia type 1A 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000483783 SCV000570761 uncertain significance not provided 2019-01-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the VRK1 gene. The K301E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The K301E variant is observed in 21/63,838 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K301E 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. This substitution occurs at a position where amino acids with similar properties to Lysine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000543393 SCV000639690 uncertain significance Pontocerebellar hypoplasia type 1 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 301 of the VRK1 protein (p.Lys301Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs149661915, ExAC 0.03%). This variant has not been reported in the literature in individuals with VRK1-related disease. ClinVar contains an entry for this variant (Variation ID: 315123). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Fulgent Genetics,Fulgent Genetics RCV000765200 SCV000896435 uncertain significance Pontocerebellar hypoplasia type 1A 2018-10-31 criteria provided, single submitter clinical testing

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