ClinVar Miner

Submissions for variant NM_000431.4(MVK):c.119G>A (p.Arg40Gln) (rs373095009)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000702475 SCV000831331 uncertain significance Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2018-01-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 40 of the MVK protein (p.Arg40Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs373095009, ExAC 0.004%). This variant has not been reported in the literature in individuals with MVK-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 glutamine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757502 SCV000885754 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing The MVK c.119G>A; p.Arg40Gln variant (rs373095009), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the general population in 2 out of 246,270 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 40 is moderately conserved but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. Pathogenic MVK variants are causative for autosomal recessive hyper-IgD syndrome (MIM: 260920) or mevalonic aciduria (MIM: 610377).

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