rs104895304
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I268V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000431.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MVK | NM_000431.4 | c.803T>C | p.Ile268Thr | missense_variant | 9/11 | ENST00000228510.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MVK | ENST00000228510.8 | c.803T>C | p.Ile268Thr | missense_variant | 9/11 | 1 | NM_000431.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152122Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251464Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135906
GnomAD4 exome AF: 0.000194 AC: 284AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.000183 AC XY: 133AN XY: 727234
GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152122Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74308
ClinVar
Submissions by phenotype
not provided Pathogenic:7
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 | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | MVK: PM3:Very Strong, PM2, PS3:Supporting - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 20, 2023 | Published functional studies demonstrate decreased mevalonate kinase activity as compared with wild type (Houten et al., 1999); 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, 35753512, 19011501, 10369261) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
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 | - - |
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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2001 | - - |
Mevalonic aciduria Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 15, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2001 | - - |
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. - |
Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MVK protein function with a negative predictive value of 80%. 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. - |
Autoinflammatory syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at