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

gnomAD frequency: 0.00156  dbSNP: rs28934897

Total submissions: 47

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627780	SCV000634151	pathogenic	Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever	2025-02-01	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). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". 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 disorder	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	2025-02-01	criteria provided, single submitter	clinical testing	MVK: PM3:Very Strong, PS3:Moderate, PM2:Supporting
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	2024-09-13	criteria provided, single submitter	clinical testing	PP4, 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	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 disorder	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
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000012705	SCV004806825	pathogenic	Hyperimmunoglobulin D with periodic fever	2024-03-26	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814886	SCV005071253	pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000221789	SCV005199301	pathogenic	not provided	2022-10-14	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000012705	SCV005367959	pathogenic	Hyperimmunoglobulin D with periodic fever	2024-07-12	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783724	SCV005397680	pathogenic	Mevalonic aciduria	2024-03-22	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at position 1129 of the coding sequence of the MVK gene that results in a valine to isoleucine amino acid change at residue 377 of the mevalonate kinase protein. This is a previously reported variant (ClinVar 11929) that has been observed in a homozygous or compound heterozygous state in individuals affected by hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) and MK enzyme deficiency (MKD) (PMID: 10369261, 10369262, 10896296, 11313769, 12444096, 15536479, 17105862, 22038276, 23979089, 24360083, 24177804, 24233262, 24470648, 24561416, 25708585, 25866490, 26986117, 27213830, 31474985, 32822427, 33917151, 34525209, 34809655, 35387795). Additionally, the homozygous state of this variant is predicted to have variable penetrance of disease (PMID: 12634869, 25708585). This variant is present in 3382 of 1612856 alleles (0.2097%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be neutral, and the Val377 residue at this position is moderately conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have found reduced or undetectable mevalonate kinase activity and MK protein expression in affected individuals (PMID: 10369261). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: BP4, PM3, PP1, PS3, PS4
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004783724	SCV005399255	pathogenic	Mevalonic aciduria	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive hyper-IgD syndrome (MIM#260920), mevalonic aciduria (MIM#610377) and autosomal dominant porokeratosis 3, multiple types (MIM#175900) (DECIPHER). (I) 0108 - This gene is associated with both recessive and dominant disease, where the same variants have been reported for both conditions. Autosomal dominant porokeratosis 3, multiple types (MIM#175900) may only manifest due to additional circumstances such as environmental factors (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32822427). This gene may be associated with a spectrum of disease, including severe perinatal presentations with hydrops (PMID: 27012807). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (221 heterozygotes, 1 homozygote). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is the most common pathogenic variant in the MVK gene and is associated with hyper-IgD syndrome (Infevers database). There are many unrelated patients affected with mevalonate kinase deficiency or hyper-IgD syndrome who were identified as compound heterozygous or homozygous for this variant (ClinVar, PMID: 32822427). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Immunoblot analysis of patient lymphocytes showed minimal MK activity (PMID: 10369261). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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/.
PreventionGenetics, part of Exact Sciences	RCV000791161	SCV004103055	pathogenic	MVK-related disorder	2024-02-08	no assertion criteria provided	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). This variant is reported in 0.24% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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.
GenomeConnect - CFC International	RCV000627780	SCV005870900	not provided	Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever		no assertion provided	phenotyping only	Variant classified as not provided and reported on 06-23-2021 by Unknown Russian Laboratory. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.