ClinVar Miner

Submissions for variant NM_000431.4(MVK):c.803T>C (p.Ile268Thr) (rs104895304)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000191109 SCV000245512 pathogenic Mevalonic aciduria; Hyperimmunoglobulin D with periodic fever 2014-09-17 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [V377I] in a 21-year-old female with FTT in infancy, childhood developmental delay, hypermobile joints, muscle soreness, fatigue, obesity, recurrent infections, anemia, anxiety and depression, overbite, flat feet, unexplained fevers, family history of EDS. Variant pathogenic in recessive state; heterozygotes are carriers.
GeneDx RCV000218157 SCV000279122 pathogenic not provided 2017-11-27 criteria provided, single submitter clinical testing The I268T pathogenic variant in the MVK gene has also been reported previously in association with HIDS. 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. I268T 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 where amino acids with similar properties to isoleucine are tolerated across species; however, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (L264F, L265P/R, D269H, S272F) have been reported in the Human Gene Mutation Database in association with Hyperimmunoglobulin D and periodic fever syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, in a study of 103 individuals who had a clinical diagnosis of HIDS, approximately 15% of patients were compound heterozygous for the the I268T and another pathogenic variant (van der Hilst, et al., 2008; Siemiatkowska et al., 2013; Thors et al., 2014).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000505909 SCV000604325 pathogenic not specified 2016-11-16 criteria provided, single submitter clinical testing
Invitae RCV000698175 SCV000826821 pathogenic Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 268 of the MVK protein (p.Ile268Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs104895304, ExAC 0.02%). This variant has been reported in several homozygous and compound heterozygous individuals affected with mevalonate kinase deficiency and hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) (PMID: 27142780, 27213830, 19011501, 11313769, 23692791, 24470648, 26116953, 21425920, 10369261, 10417275, 10401001). ClinVar contains an entry for this variant (Variation ID: 11932). Experimental studies have shown that this missense change leads to severely reduced expression and enzymatic activity of mevalonate kinase (PMID: 10417275, 10401001, 10369261). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000218157 SCV001746157 pathogenic not provided 2021-05-01 criteria provided, single submitter clinical testing
OMIM RCV000012709 SCV000032944 pathogenic Hyperimmunoglobulin D with periodic fever 2001-04-01 no assertion criteria provided literature only
OMIM RCV000012710 SCV000032945 pathogenic Mevalonic aciduria 2001-04-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000012709 SCV000115986 not provided Hyperimmunoglobulin D with periodic fever no assertion provided not provided
Institute of Human Genetics, Klinikum rechts der Isar RCV000012710 SCV000680305 pathogenic Mevalonic aciduria 2017-11-15 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000218157 SCV001808261 pathogenic not provided no assertion criteria provided clinical testing

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