ClinVar Miner

Submissions for variant NM_003384.3(VRK1):c.1021C>T (p.Leu341Phe) (rs139734064)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000518980 SCV000620507 uncertain significance not provided 2018-06-11 criteria provided, single submitter clinical testing The L341F variant in the VRK1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the L341F variant is observed in 18/10390 (0.17%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). The L341F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret L341F as a variant of uncertain significance.
Invitae RCV000553451 SCV000639685 uncertain significance Pontocerebellar hypoplasia type 1 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 341 of the VRK1 protein (p.Leu341Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs139734064, ExAC 0.2%). This variant has not been reported in the literature in individuals with VRK1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Illumina Clinical Services Laboratory,Illumina RCV001118139 SCV001276402 uncertain significance Pontocerebellar hypoplasia type 1A 2018-01-12 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.

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