chr12-109591275-T-C
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000431.4(MVK):c.803T>C(p.Ile268Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000192 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
MVK
NM_000431.4 missense
NM_000431.4 missense
Scores
7
11
1
Clinical Significance
Conservation
PhyloP100: 4.63
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a helix (size 25) in uniprot entity KIME_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000431.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.895
PP5
Variant 12-109591275-T-C is Pathogenic according to our data. Variant chr12-109591275-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 11932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109591275-T-C is described in Lovd as [Pathogenic]. Variant chr12-109591275-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152122Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
26
AN:
152122
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251464Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135906
GnomAD3 exomes
AF:
AC:
38
AN:
251464
Hom.:
AF XY:
AC XY:
20
AN XY:
135906
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000194 AC: 284AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.000183 AC XY: 133AN XY: 727234
GnomAD4 exome
AF:
AC:
284
AN:
1461870
Hom.:
Cov.:
33
AF XY:
AC XY:
133
AN XY:
727234
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000171 AC: 26AN: 152122Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74308
GnomAD4 genome
AF:
AC:
26
AN:
152122
Hom.:
Cov.:
33
AF XY:
AC XY:
11
AN XY:
74308
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
3
ExAC
AF:
AC:
13
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:20Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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 | GeneDx | Aug 19, 2024 | In a study of 103 individuals who had a clinical diagnosis of hyper-IgD syndrome, approximately 15% of patients were compound heterozygous for the I268T variant and another pathogenic variant (PMID: 19011501, 24084495, 24470648); Published functional studies demonstrate decreased mevalonate kinase activity as compared with wild type (PMID: 10369261); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24088041, 11313768, 15536479, 29290516, 34525209, 34145613, 32060250, 23692791, 21425920, 10369262, 10417275, 11313769, 25897835, 24470648, 26116953, 26990548, 18839211, 10896296, 24084495, 31028937, 31474985, 31589614, 36242899, 35916082, 31964843, 37700301, 33815380, 35753512, 19011501, 10369261) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2025 | MVK: PM3:Very Strong, PM2, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 15, 2023 | PP3, PP4, PM2, PM3, PS3, PS4 - |
Hyperimmunoglobulin D with periodic fever Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Mar 24, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2001 | - - |
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2023 | Variant summary: MVK c.803T>C (p.Ile268Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251464 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MVK causing Hyper-IgD syndrome (0.00015 vs 0.0056), allowing no conclusion about variant significance. c.803T>C has been reported in the literature in multiple individuals affected with Hyper-IgD syndrome (e.g. Houten_1999, Cuisset_2001, Simon_2006). 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, finding that the variant results in <10% of normal activity (Houten_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10369261, 11313769, 16234278). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Mevalonic aciduria Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 15, 2017 | - - |
Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 03, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2025 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 268 of the MVK protein (p.Ile268Thr). This variant is present in population databases (rs104895304, gnomAD 0.03%). This missense change has been observed in individuals with mevalonate kinase deficiency and hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) (PMID: 10369261, 10401001, 10417275, 11313769, 19011501, 21425920, 23692791, 24470648, 26116953, 27142780, 27213830). ClinVar contains an entry for this variant (Variation ID: 11932). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MVK protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MVK function (PMID: 10369261, 10401001, 10417275). 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 | Nov 16, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 25, 2022 | The c.803T>C (p.I268T) alteration is located in exon 9 (coding exon 8) of the MVK gene. This alteration results from a T to C substitution at nucleotide position 803, causing the isoleucine (I) at amino acid position 268 to be replaced by a threonine (T). _x000D_ _x000D_ Based on the available evidence, the c.803T>C p.I268T alteration is classified as pathogenic for autosomal recessive mevalonate kinase deficiency; however, the association of this alteration with autosomal dominant MVK-related porokeratosis is unlikely. Based on data from gnomAD, the C allele has an overall frequency of 0.02% (44/282850) total alleles studied. The highest observed frequency was 0.03% (36/129164) of European (non-Finnish) alleles. This alteration has been reported as homozygous and compound heterozygous in multiple unrelated individuals with mevalonate kinase deficiency (Houten, 1999; Houten, 1999; Hinson, 1999; Cuisset, 2001; Sornsakrin, 2009; Gençpnar, 2012; Siemiatkowska, 2013; Jeyaratnam, 2016; Ter Haar, 2016; Dunn, 2018; Munoz, 2019; Correa, 2020; Brennenstuhl, 2021; Steiner, 2011). This amino acid position is well conserved in available vertebrate species. In two different studies involving patient cell lines, cells from two different patients (one homozygote and one compound heterozygote) showed reduced MKase enzymatic activity levels (Houten, 1999; Hinson, 1999). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
MVK-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jun 10, 2022 | The c.803T>C;p.(Ile268Thr) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clivar ID: 11932; PMID: 33917151; 24470648; 28359055; 24084495; 11313769) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28359055) - PS3_moderate. The variant is present at low allele frequencies population databases (rs104895304– gnomAD 0.001709%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Ile268Thr) was detected in trans with a Pathogenic variant (PMID: 33917151; 24470648; 11313769) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 24084495) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic - |
Hyperimmunoglobulin D with periodic fever;C1959626:Mevalonic aciduria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 17, 2014 | This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [V377I] 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 | Jan 01, 2020 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;T;T;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;H
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.
Sift4G
Uncertain
D;D;D;D
Polyphen
P;D;D;P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at