ClinVar Miner

Submissions for variant NM_000431.4(MVK):c.608T>C (p.Val203Ala) (rs104895332)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217732 SCV000279119 pathogenic not provided 2015-11-19 criteria provided, single submitter clinical testing To our knowledge, the V203A variant has not been published as pathogenic or benign variant. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V203A 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 that is conserved across species; however, in-silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (G202R, N205D, T209A, G211E/A) have been reported in the Human Gene Mutation Database in association with MVK-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available evidence, this variant is considered to be likely pathogenic.
Invitae RCV000799676 SCV000939351 likely pathogenic Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 203 of the MVK protein (p.Val203Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs104895332, ExAC 0.002%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in two siblings affected with mevalonate kinase deficiency (PMID: 15188372). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. In addition, it has been reported in an individual with periodic fever (PMID: 29047407). ClinVar contains an entry for this variant (Variation ID: 97601). Experimental studies have shown that patient cells that carry this missense change in addition to the p.Ile268Thr missense change exhibit minimal mevalonate kinase activity (PMID: 15188372). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000217732 SCV001716137 likely pathogenic not provided 2019-08-03 criteria provided, single submitter clinical testing PM3, PP3, PP4, PS3_moderate
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083853 SCV000115958 not provided Hyperimmunoglobulin D with periodic fever no assertion provided not provided

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