rs28934897

chr12-109596515-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1 PP5_Very_Strong BP4

The NM_000431.4(MVK):c.1129G>A(p.Val377Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0021 in 1,612,856 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (3 hom.)
• Consequence: MVK NM_000431.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:40 O:1
• Conservation: PhyloP100: 5.08

Genes affected

MVK (HGNC:7530): (mevalonate kinase) This gene encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is a key intermediate, and mevalonate kinase a key early enzyme, in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene results in mevalonic aciduria, a disease characterized psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000431.4
• PP5: Variant 12-109596515-G-A is Pathogenic according to our data. Variant chr12-109596515-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109596515-G-A is described in Lovd as [Pathogenic]. Variant chr12-109596515-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.01983887).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVK	NM_000431.4	c.1129G>A	p.Val377Ile	missense_variant	11/11	ENST00000228510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000228510.8	c.1129G>A	p.Val377Ile	missense_variant	11/11	1	NM_000431.4	P1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00158 AC: 393 AN: 249414 Hom.: 0 AF XY: 0.00160 AC XY: 216 AN XY: 135048

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00142

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00216 AC: 3159 AN: 1460542 Hom.: 3 Cov.: 31 AF XY: 0.00210 AC XY: 1523 AN XY: 726670

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00251

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74474

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00190 Hom.: 1

Bravo AF: 0.00134

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00140 AC: 170

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:40 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperimmunoglobulin D with periodic fever Pathogenic:16

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 11, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong, PP1 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 03, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 28, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 28, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 08, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3. -
Pathogenic, no assertion criteria provided	clinical testing	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	May 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jan 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Aug 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Feb 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Mar 10, 2022	- -

not provided Pathogenic:14

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 02, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MVK: PM3:Very Strong, PS3:Moderate, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 10, 2022	PS3, PS4, PM3 -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2023	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) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

MVK-related disorder Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 08, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Feb 12, 2024	- -

Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	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/. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 05, 2018

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. -

Porokeratosis 3, disseminated superficial actinic type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Apr 19, 2019

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2021

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. -

Hyperimmunoglobulin D with periodic fever;C1959626:Mevalonic aciduria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 01, 2015

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. -

Autoinflammatory syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	14
Dann	Uncertain	0.98
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;.;.;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.020	T;T;T;T;T
MetaSVM	Uncertain	0.071	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.86	N;N;N;.;.
REVEL	Uncertain	0.55
Sift	Benign	0.10	T;T;T;.;.
Sift4G	Uncertain	0.036	D;T;D;D;T
Polyphen		0.33, 0.45	.;B;B;B;B
Vest4		0.21
MVP		0.77
MPC		0.30
ClinPred		0.026	T
GERP RS		3.2
Varity_R		0.095
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28934897; hg19: chr12-110034320; COSMIC: COSV57332186;