ClinVar Miner

Submissions for variant NM_000431.4(MVK):c.1139A>G (p.His380Arg) (rs104895324)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000690628 SCV000818325 pathogenic Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2020-07-23 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 380 of the MVK protein (p.His380Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs104895324, ExAC 0.008%). This variant has been reported in combination with another MVK variant in several individuals affected with hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) (PMID: 15804303, 19011501, 21399979, 24561416, 29047407), has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an affected individual (Invitae). ClinVar contains an entry for this variant (Variation ID: 97569). Algorithms developed to predict the effect of missense changes on protein structure and function 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757501 SCV000885753 uncertain significance not provided 2018-04-08 criteria provided, single submitter clinical testing The MVK c.1139A>G; p.His380Arg variant (rs104895324) is reported in the medical literature in individuals with mevalonate kinase deficiency, hyperimmunoglobulinemia D and periodic fever syndrome (Shendi 2014, Tahara 2011, Wickiser 2005). The variant is reported in the ClinVar database (Variation ID: 97569). This variant is found in the non-Finnish European population with an overall allele frequency of 0.007% (10/126246 alleles) in the Genome Aggregation Database. The histidine at codon 380 is moderately conserved across species but computational algorithms (PolyPhen-2, SIFT) predict conflicting effects of this variant on protein structure/function. Considering available information, the clinical significance of this variant cannot be determined with certainty. Pathogenic MVK variants are causative for autosomal recessive hyper IgD syndrome (MIM: 260920) and mevalonic aciduria (MIM: 610377). References: Shendi HM et al. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol. 2014 Mar;20(2):103-5. Tahara M et al. Patient with neonatal-onset chronic hepatitis presenting with mevalonate kinase deficiency with a novel MVK gene mutation. Mod Rheumatol. 2011 Dec;21(6):641-5. Wickiser JE and Saulsbury FT. Henoch-Schonlein purpura in a child with hyperimmunoglobulinemia D and periodic fever syndrome. Pediatr Dermatol. 2005 Mar-Apr;22(2):138-41.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083821 SCV000115923 not provided Hyperimmunoglobulin D with periodic fever no assertion provided not provided

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