ClinVar Miner

Submissions for variant NM_000431.4(MVK):c.1129G>A (p.Val377Ile) (rs28934897)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000191108 SCV000245511 pathogenic Mevalonic aciduria; Hyperimmunoglobulin D with periodic fever 2015-07-01 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 [I268T] 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 RCV000221789 SCV000279123 pathogenic not provided 2018-05-15 criteria provided, single submitter clinical testing The V377I variant in the MVK gene has been reported previously in association with autosomal recessive hyper-IgD syndrome (HIDS) in multiple unrelated individuals (Houten et al., 1999; Cuisset et al., 2001; Thors et al., 2014; Messer et al., 2016). The V377I variant has been identified in 90% of HIDS patients, but was found homozygous in at least one clinically asymptomatic individual (Messer et al., 2016). Although not present in the homozygous state in any control individuals, V377I is observed in 303/126,088 alleles (0.24%) from individuals of non-Finnish European background, and 438/275,368 global alleles (0.16%), in large population cohorts (Lek et al., 2016). The V377I variant is a conservative amino acid substitution, which occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, in vitro studies indicate that V377I leads to a decrease in enzyme activity and decreased stability when expressed in E. coli (Houten et al., 1999). Missense variants in nearby residues (G376S, G376V, S378P, I379N, H380R) have been reported in the Human Gene Mutation Database in association with MVK-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret V377I as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000221789 SCV000331859 pathogenic not provided 2017-08-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000012705 SCV000375799 pathogenic Hyperimmunoglobulin D with periodic fever 2017-08-28 criteria provided, single submitter clinical testing The MVK c.1129G>A (p.Val377Ile) missense variant is very common and occurs in approximately 90% of individuals with hyper IgD syndrome (HIDS) (Messer et al. 2016). Across a selection of the available literature, the p.Val377Ile variant was reported in a total of 28 symptomatic patients with HIDS, including in eight homozygotes, 16 compound heterozygotes, and four heterozygotes in whom a second variant was not identified (Lainka et al. 2012; Parvaneh et al. 2014; Chandrakasan et al. 2014; Moussa et al. 2015; De Pieri et al. 2015; Messer et al. 2016). The p.Val377Ile variant was also reported in five asymptomatic individuals who were either homozygous or compound heterozygous for the variant (Lainka et al. 2012; Messer et al. 2016), though this is consistent with the mild phenotype and reduced penetrance reported by Houten et al. (2003). Control data are not available in these studies, but the variant is reported at a frequency of 0.00221 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Val377Ile variant is classified as pathogenic for hyper IgD syndrome, though many individuals with this variant may present with a mild phenotype or may be asymptomatic. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000012705 SCV000538050 pathogenic Hyperimmunoglobulin D with periodic fever 2016-03-30 criteria provided, single submitter clinical testing The c.1129G>A (p.Val377Ile) missense variant in the MVK gene is a known common variant that has been previously reported in numerous individuals affected with Hyper IgD Syndrome (Houten et al., 1999; Houten et al., 2003; Mandey et al., 2006; Gençpınar et al., 2012; Cantarini et al., 2013; Levy et al., 2013; Shendi et al., 2014; Moussa et al., 2015).This variant has also been reported in trans with other known pathogenic variants (His20Pro, Ile1268Thr, Lys13Aspfs*66, Pro167Leu) (Houten et al.,1999; Gençpınar et al., 2012). Functional studies have shown reduced or undetectable mevalonate kinase activity and protein expression in affected individuals, indicating this variant likely affects protein stability and function (Houten et al., 1999). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.221%; 1000 Genomes = NA; and ExAC = 0.196%). A reputable clinical diagnostic laboratory (Baylor Miraca Genetics Laboratories) has classified this variant as Pathogenic. Therefore, this collective evidence supports the classification of the c.1129G>A (p.Val377Ile) as a recessive Pathogenic variant for Hyper IgD Syndrome. We have confirmed this finding in our laboratory using Sanger sequencing.
Genetic Services Laboratory, University of Chicago RCV000012705 SCV000595874 pathogenic Hyperimmunoglobulin D with periodic fever 2017-04-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999977 SCV000604326 pathogenic not specified 2018-07-05 criteria provided, single submitter clinical testing The MVK c.1129G>A;p.Val377Ile variant (rs28934897) is described in the medical literature in both the homozygous and compound heterozygous state in individuals with hyperimmunoglobulin D syndrome (HIDS) with reduced mevalonate kinase activity and has been implicated as the most common pathogenic HIDS variant (Houten 1999, Houten 2003). The variant is listed in the ClinVar database (Variation ID: 11929) and in the Genome Aggregation Database with an allele frequency of 0.16% (438/275368 alleles). Considering available information, this variant is classified as pathogenic. Pathogenic MVK variants are causative for autosomal recessive hyperimmunoglobulin D syndrome (HIDS, MIM: 260920) and mevalonic aciduria (MIM: 610377). References: Houten SM et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999 22(2):175-7. Houten SM et al. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet. 2003 11(2):196-200.
Invitae RCV000627780 SCV000634151 pathogenic Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 377 of the MVK protein (p.Val377Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs28934897, ExAC 0.2%). This variant has been reported as homozygous or compound heterozygous in numerous individuals and families affected with hyper IgD syndrome (HIDS), and is one of the most commonly reported variants found in HIDS patients (PMID: 12634869, 26977311, 15536479, 11313769, 10369261). Asymptomatic individuals homozygous or compound heterozygous for this variant have also been reported, suggesting this variant may be associated with a mild phenotype or reduced penetrance (PMID: 12634869, 26977311). ClinVar contains an entry for this variant (Variation ID: 11929). Experimental studies have shown that this missense change results in reduced MVK enzymatic activity (PMID: 10369261, 26977311). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000012705 SCV000712172 pathogenic Hyperimmunoglobulin D with periodic fever 2016-05-28 criteria provided, single submitter clinical testing The p.Val377Ile variant in MVK has been identified in 0.14% (170/120,578) of chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs28934897). This variant is the most frequent pathogenic variant in Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) (Houten 1999, Cuis set 2001, Houten 2003). It has been demonstrated to lead to reduced enzymatic ac tivity in vitro (Houten 1999). In summary, this variant meets our criteria to be classified as pathogenic for hyperimmunoglobulinemia D syndrome (HIDS) in an au tosomal recessive manner, based on biallelic observations in patients and functi onal evidence.
Fulgent Genetics,Fulgent Genetics RCV000627780 SCV000893959 pathogenic Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000221789 SCV000928151 pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000791161 SCV000930436 uncertain significance MVK-Related Disorders 2019-04-27 criteria provided, single submitter clinical testing
Mendelics RCV000012705 SCV001138812 pathogenic Hyperimmunoglobulin D with periodic fever 2019-05-28 criteria provided, single submitter clinical testing
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000012705 SCV001156405 pathogenic Hyperimmunoglobulin D with periodic fever 2019-02-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000221789 SCV001246722 pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000999977 SCV001251719 uncertain significance not specified 2020-05-03 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000012705 SCV001366331 likely pathogenic Hyperimmunoglobulin D with periodic fever 2019-04-08 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000221789 SCV001447867 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV001270083 SCV001448885 pathogenic Porokeratosis 3, disseminated superficial actinic type 2019-04-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV000012705 SCV001520663 pathogenic Hyperimmunoglobulin D with periodic fever 2020-06-03 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic RCV000221789 SCV001716138 pathogenic not provided 2021-03-30 criteria provided, single submitter clinical testing PS3, PS4, PM3, PP4
Undiagnosed Diseases Network,NIH RCV000012705 SCV001736848 pathogenic Hyperimmunoglobulin D with periodic fever 2019-01-17 criteria provided, single submitter clinical testing
OMIM RCV000012705 SCV000032940 pathogenic Hyperimmunoglobulin D with periodic fever 2005-03-01 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000221789 SCV001548926 pathogenic not provided no assertion criteria provided clinical testing The MVK p.Val325Ile variant was identified in 23 of 58 proband chromosomes (frequency: 0.43) from individuals or families with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) (Houten_1999_PMID:10369261; Cuisset_2001_PMID:11313769). The variant was also identified in dbSNP (ID: rs28934897), ClinVar (classified as pathogenic by Invitae, GeneDx and eight other laboratories) and LOVD 3.0 (classified as pathogenic and likely pathogenic). The variant was identified in control databases in 443 of 280790 chromosomes at a frequency of 0.001578 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 303 of 128360 chromosomes (freq: 0.002361), Latino in 50 of 35436 chromosomes (freq: 0.001411), European (Finnish) in 33 of 23962 chromosomes (freq: 0.001377), Other in 9 of 7198 chromosomes (freq: 0.00125), South Asian in 28 of 30616 chromosomes (freq: 0.000915), Ashkenazi Jewish in 8 of 10360 chromosomes (freq: 0.000772), African in 10 of 24932 chromosomes (freq: 0.000401), and East Asian in 2 of 19926 chromosomes (freq: 0.0001). The V325I variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val325 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. However, functional studies expressing cDNA constructs containing the V325I variant in E. coli have demonstrated decreased mevalonate kinase (MK) protein activity compared to wildtype (Houten_1999_PMID:10369261). Decreased MK activity was also found in lymphocytes and fibroblasts from patients with the V325I variant (Houten_1999_PMID:10369261). Interestingly, this variant has been reported in the homozygous state in two sisters, one affected with HIDS and the other who was asymptomatic, therefore suggesting that other genetic factors may influence the presentation of HIDS in individuals with the V325I variant (Messer_2016_PMID:26977311). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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