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

gnomAD frequency: 0.00005  dbSNP: rs104895324

Total submissions: 6

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	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 380 of the MVK protein (p.His380Arg). This variant is present in population databases (rs104895324, gnomAD 0.008%). This missense change has been observed in individual(s) with hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) (PMID: 15804303, 19011501, 21399979, 24561416, 29047407). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 97569). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MVK protein function with a positive predictive value of 95%. 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.
PreventionGenetics, part of Exact Sciences	RCV003398690	SCV004106061	likely pathogenic	MVK-related condition	2023-04-10	criteria provided, single submitter	clinical testing	The MVK c.1139A>G variant is predicted to result in the amino acid substitution p.His380Arg. This variant has been reported, along other variants in MVK in the compound heterozygous state and phase unknown, in individuals with hyper-IgD and periodic fever syndrome (HIDS) (Wickiser and Saulsbury. 2005. PubMed ID: 15804303; Tahara et al. 2011. PubMed ID: 21399979; Shendi et al. 2014. PubMed ID: 24561416; Papa et al. 2017. PubMed ID: 29047407). A long-term study of 103 individuals with hyperimmunoglobulinemia D syndrome found that the c.1139A>G (p.His380Arg) was present at an allele frequency of 1.5% and was a prevalent variant seen in patients (van der Hilst et al. 2008. PubMed ID: 19011501). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-110034330-A-G) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from pathogenic to likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/97569/). This variant is interpreted as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000757501	SCV004226873	likely pathogenic	not provided	2022-04-27	criteria provided, single submitter	clinical testing	PP3, PM1, PM2_supporting, PS4_moderate
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083821	SCV000115923	not provided	Hyperimmunoglobulin D with periodic fever		no assertion provided	not provided
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000083821	SCV002029154	likely pathogenic	Hyperimmunoglobulin D with periodic fever	2021-08-05	no assertion criteria provided	clinical testing