ClinVar Miner

Submissions for variant NM_000431.4(MVK):c.346T>C (p.Tyr116His) (rs104895382)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000220019 SCV000279117 pathogenic not provided 2017-10-25 criteria provided, single submitter clinical testing The Y116H missense change has been reported previously in individuals with mevalonate kinase deficiency (MKD) or hyperimmunoglobulin D syndrome (Samkari et al., 2010; Levy et al., 2013; Leyva-Vega et al., 2011). It was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. Y116H 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 that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, missense variants in nearby residues (L117P, I119M) 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.
Invitae RCV000645101 SCV000766843 pathogenic Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2020-06-20 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 116 of the MVK protein (p.Tyr116His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs104895382, ExAC 0.05%). This variant has been reported as homozygous and as compound heterozygous with other rare MVK missense variants in several individuals affected with melvalonic aciduria or hyper IgD (HIDS) syndrome (PMID: 23979089, 20194276, 21548022, 29047407, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This finding is consistent with autosomal recessive inheritance and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 97581). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000083833 SCV001521441 pathogenic Hyperimmunoglobulin D with periodic fever 2020-07-08 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083833 SCV000115935 not provided Hyperimmunoglobulin D with periodic fever no assertion provided not provided

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