ClinVar Miner

Submissions for variant NM_000431.4(MVK):c.709A>T (p.Thr237Ser) (rs104895366)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480950 SCV000568224 pathogenic not provided 2017-02-16 criteria provided, single submitter clinical testing The T237S missense variant in the MVK gene has been reported previously in association with MKD disorder (Rolland et al., 2005; Jesus et al., 2012; Ter Haar et al., 2016), and its presence is consistent with the diagnosis in this patient. The T237S variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). The T237S 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 and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies confirm that T237S results in significantly lowered MK enzyme activity (Rolland et al., 2005; Mandey et al., 2006). Missense variants in the same (T237N) and other nearby residues (L234P, R241C) have been reported in the Human Gene Mutation Database in association with mevalonic kinase deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000480950 SCV001246719 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Invitae RCV001381669 SCV001580161 pathogenic Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2020-01-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 237 of the MVK protein (p.Thr237Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs104895366, ExAC 0.003%). This variant has been observed to be homozygous and in combination with other MVK variants in several individuals affected with Mevalonate kinase deficiency (PMID: 16835861, 28814775, 16197847, 31096039, 21708801). ClinVar contains an entry for this variant (Variation ID: 97612). 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. For these reasons, this variant has been classified as Pathogenic.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083864 SCV000115969 not provided Hyperimmunoglobulin D with periodic fever no assertion provided not provided

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