ClinVar Miner

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

gnomAD frequency: 0.00156  dbSNP: rs28934897
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Total submissions: 40
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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 2023-06-19 criteria provided, single submitter clinical testing Published functional studies indicate that p.(V377I) leads to a decrease in enzyme activity and decreased stability when expressed in E. coli (Houten et al., 1999); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23692791, 12634869, 21228398, 23979089, 24561416, 25708585, 30030262, 24177804, 19011501, 34525209, 34809655, 24360083, 24470648, 10369262, 10369261, 15188372, 26300074, 26633545, 26977311, 11313769, 26116953, 15657603, 27899390, 13130485, 26990548, 28638818, 18839211, 24716072, 15536479, 25866490, 24233262, 22038276, 30609409, 26620804, 29290516, 10896296, 30148429, 31474985, 30783801, 31664448, 34573280, 34426522, 34054914, 31589614, 32822427, 32888943, 35418827, 33917151, 35163749, 17105862, 26986117, 35387795, 35753512)
Eurofins Ntd Llc (ga) RCV000221789 SCV000331859 pathogenic not provided 2017-08-18 criteria provided, single submitter clinical testing
Illumina Laboratory Services, 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 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 377 of the MVK protein (p.Val377Ile). This variant is present in population databases (rs28934897, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hyper IgD syndrome (HIDS), and is one of the most commonly reported variants found in HIDS patients (PMID: 10369261, 11313769, 12634869, 15536479, 26977311). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11929). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects MVK function (PMID: 10369261, 26977311). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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 pathogenic MVK-Related Disorders 2024-02-12 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 Center for Human Genetics Tuebingen RCV000221789 SCV001246722 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing MVK: PM3:Very Strong, PM2, PS3:Moderate, PP1
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 2023-03-01 criteria provided, single submitter clinical testing PM2, PM3, PS3, PS4
Undiagnosed Diseases Network, NIH RCV000012705 SCV001736848 pathogenic Hyperimmunoglobulin D with periodic fever 2019-01-17 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000221789 SCV002017646 pathogenic not provided 2023-10-31 criteria provided, single submitter clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV000012705 SCV002104233 likely pathogenic Hyperimmunoglobulin D with periodic fever 2022-03-10 criteria provided, single submitter clinical testing
DASA RCV000791161 SCV002526420 pathogenic MVK-Related Disorders 2022-06-10 criteria provided, single submitter clinical testing The c.1129G>A;p.(Val377Ile) missense change has been observed in affected individual(s)(PMID: 33917151; 26986117; 15536479; 32822427; 17105862) - PS4. The p.(Val377Ile) was detected in trans with a Pathogenic variant (PMID: 33917151; 26986117; 15536479; 32822427; 17105862) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32822427; 17105862) - PP1 andallele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is Pathogenic
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002262563 SCV002542319 pathogenic Autoinflammatory syndrome 2022-03-17 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital RCV000221789 SCV002818165 pathogenic not provided 2022-12-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV002512987 SCV003740446 pathogenic Inborn genetic diseases 2021-07-22 criteria provided, single submitter clinical testing The c.1129G>A (p.V377I) alteration is located in exon 11 (coding exon 10) of the MVK gene. This alteration results from a G to A substitution at nucleotide position 1129, causing the valine (V) at amino acid position 377 to be replaced by an isoleucine (I). Based on the available evidence, this variant is pathogenic for mevalonate kinase deficiency (AR); however, it is unlikely to be causative of MVK-related porokeratosis (AD). Based on data from the Genome Aggregation Database (gnomAD), the MVK c.1129G>A alteration was observed in 0.16% (443/280790) of total alleles studied, with a frequency of 0.24% (303/128360) in the European (non-Finnish) subpopulation. This common mutation has been reported in individuals with clinical and biochemical features consistent with mevalonate kinase deficiency in both the homozygous and compound heterozygous state (Cuisset, 2001; Drenth, 1999; Houten, 1999; Munoz, 2019); however, asymptomatic individuals have also been reported (Lainka, 2012; Messer, 2016). Functional studies showed that this alteration results in reduced enzyme activity (Houten, 1999; Messer, 2016). Based on the available evidence, this alteration is classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000012705 SCV003807561 pathogenic Hyperimmunoglobulin D with periodic fever 2022-08-11 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong, PP1 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012705 SCV003928976 pathogenic Hyperimmunoglobulin D with periodic fever 2023-04-14 criteria provided, single submitter clinical testing Variant summary: MVK c.1129G>A (p.Val377Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 249414 control chromosomes, predominantly at a frequency of 0.0023 within the Non-Finnish European subpopulation in the gnomAD database. c.1129G>A has been reported in the literature in multiple individuals affected with Hyper-IgD syndrome (HIDS), including in cases where it was in trans with a pathogenic variant and it has been found to segregate with disease (e.g. Houten_1999, Cuisset_2001, Govindaraj_2020). It is reportedly the most frequently occurring variant identified in HIDS patients (Houten_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant is associated with an MK activity of approximately 40% of WT in E.coli lysates and that it was undetectable by immunoblot in fibroblast lysates from HIDS patients, suggesting it also impacts protein stability (Houten_1999). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and the majority classified it as pathogenic (n=27)/likely pathogenic (n=2), with the remaining classifying it as VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center RCV000012705 SCV004031068 pathogenic Hyperimmunoglobulin D with periodic fever 2023-08-31 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003398489 SCV004103055 pathogenic MVK-related condition 2023-06-09 criteria provided, single submitter clinical testing The MVK c.1129G>A variant is predicted to result in the amino acid substitution p.Val377Ile. This is a well-documented pathogenic variant for Hyper-IgD syndrome (HIDS) and has been reported in ~90% of the HIDS cases, both in the homozygous and compound heterozygous states (Messer et al. 2016. PubMed ID: 26977311; Schlabe et al. 2016. PubMed ID: 27899390; Houten et al. 2003. PubMed ID: 12634869). Although, there are occasional reports of this variant in patients with mevalonic aciduria (MA) (Favier and Schulert 2016. PubMed ID: 27499643), functional studies did not indicate a profound enzyme deficiency as expected in patients with MA (Cuisset et al. 2001. PubMed ID: 11313769). In addition, this variant is known for its reduced penetrance, leading to a mild or absent phenotype (Houten et al. 2003. PubMed ID: 12634869). In ClinVar, it is classified as a pathogenic variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/11929/). Taken together, this variant is considered a pathogenic variant for HIDS, but its role in mevalonic aciduria is uncertain.
OMIM RCV000012705 SCV000032940 pathogenic Hyperimmunoglobulin D with periodic fever 2013-09-01 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000221789 SCV001740681 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000221789 SCV001918026 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000221789 SCV001927500 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000221789 SCV001957696 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000221789 SCV001968606 pathogenic not provided no assertion criteria provided clinical testing
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska" RCV000012705 SCV002573426 pathogenic Hyperimmunoglobulin D with periodic fever 2022-05-01 no assertion criteria provided clinical testing
GenomeConnect - Brain Gene Registry RCV000627780 SCV003931223 not provided Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever no assertion provided phenotyping only Variant classified as Pathogenic and reported on 12-06-2016 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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