Submissions for variant NM_000431.4(MVK):c.564G>A (p.Trp188Ter)

gnomAD frequency: 0.00001  dbSNP: rs104895311

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725893	SCV000340299	pathogenic	not provided	2016-03-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000725893	SCV001167684	pathogenic	not provided	2019-03-24	criteria provided, single submitter	clinical testing	The W188X variant in the MVK gene has been reported previously with a second variant in the MVK gene in association hyper-IgD syndrome (Saulsbury, 2003; Stojanov et al., 2004). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W188X variant is not observed in large population cohorts (Lek et al., 2016). We interpret W188X as a pathogenic variant.
Invitae	RCV001381668	SCV001580160	pathogenic	Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever	2023-09-19	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with mevalonate kinase deficiency (PMID: 15188372). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 97597). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp188*) in the MVK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MVK are known to be pathogenic (PMID: 16835861, 17105862, 23834120).
Revvity Omics, Revvity	RCV000725893	SCV002017645	pathogenic	not provided	2020-11-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725893	SCV002049395	pathogenic	not provided	2021-02-11	criteria provided, single submitter	clinical testing	The MVK p.Trp188Ter variant (rs104895311), has been previously reported in an individual included in a hyperimmunoglobulinemia D cohort who also carried the pathogenic p.Val377Ile variant (Stojanov 2004). This variant introduces a stop codon in exon 6 of 11, and is expected to result in a truncated or absent protein product. This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Based on the available information, this variant is considered pathogenic. References: Stojanov et al. Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: a low-penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa. Arthritis Rheum. 2004 Jun;50(6):1951-8.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262661	SCV002542335	pathogenic	Autoinflammatory syndrome	2019-07-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001381668	SCV002809137	pathogenic	Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever	2021-10-26	criteria provided, single submitter	clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083849	SCV000115952	not provided	Hyperimmunoglobulin D with periodic fever		no assertion provided	not provided