ClinVar Genomic variation as it relates to human health
NM_000431.4(MVK):c.59A>C (p.His20Pro)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000431.4(MVK):c.59A>C (p.His20Pro)
Variation ID: 11931 Accession: VCV000011931.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.11 12: 109574881 (GRCh38) [ NCBI UCSC ] 12: 110012686 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 6, 2014 Apr 15, 2024 Sep 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000431.4:c.59A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000422.1:p.His20Pro missense NM_001114185.3:c.59A>C NP_001107657.1:p.His20Pro missense NM_001301182.2:c.59A>C NP_001288111.1:p.His20Pro missense NC_000012.12:g.109574881A>C NC_000012.11:g.110012686A>C NG_007096.1:g.3617T>G NG_007702.1:g.6187A>C LRG_156:g.6187A>C LRG_156t1:c.59A>C LRG_156p1:p.His20Pro Q03426:p.His20Pro - Protein change
- H20P
- Other names
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- Canonical SPDI
- NC_000012.12:109574880:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MVK | - | - |
GRCh38 GRCh37 |
652 | 747 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
no assertion criteria provided
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Aug 1, 1999 | RCV000012707.23 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 1, 1999 | RCV000012708.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 29, 2023 | RCV001240497.3 | |
Pathogenic (4) |
criteria provided, single submitter
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Jun 1, 2018 | RCV001093432.19 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jun 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250409.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mevalonic aciduria
Hyperimmunoglobulin D with periodic fever Porokeratosis 3, disseminated superficial actinic type
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001413447.2
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD … (more)
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 20 of the MVK protein (p.His20Pro). This missense change has been observed in individual(s) with autosomal recessive mevalonate kinase deficiency (PMID: 10369261, 10896296, 16835861). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 11931). 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 expected to disrupt MVK protein function. Experimental studies have shown that this missense change affects MVK function (PMID: 10369261). This variant disrupts the p.His20 amino acid residue in MVK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11313769, 15536479, 27213830, 28501347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926662.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(Aug 01, 1999)
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no assertion criteria provided
Method: literature only
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HYPER-IgD SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032942.8
First in ClinVar: Apr 04, 2013 Last updated: Jun 10, 2022 |
Comment on evidence:
Hyper-IgD Syndrome In 2 patients with the hyper-IgD syndrome (HIDS; 260920), Houten et al. (1999) found the V377I mutation (251170.0002) in compound heterozygous state with … (more)
Hyper-IgD Syndrome In 2 patients with the hyper-IgD syndrome (HIDS; 260920), Houten et al. (1999) found the V377I mutation (251170.0002) in compound heterozygous state with a his20-to-pro (H20P) mutation. Mevalonic Aciduria In a patient with mild mevalonic aciduria (MEVA; 610377), Houten et al. (1999) found compound heterozygosity for an A-to-C transversion at nucleotide 59, resulting in a histidine-to-proline substitution at codon 20. The other mutation was a G-to-A transition at nucleotide 1000, resulting in an ala334-to-thr (A334T; 251170.0006) substitution. The patient presented at 6 years of age with cerebellar ataxia, hypotonia, and elevated creatine kinase activity and was still alive at 20 years of age. Nuclear magnetic resonance and computed tomography of the brain revealed cerebellar hypoplasia and an enlarged fourth ventricle. (less)
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Pathogenic
(Aug 01, 1999)
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no assertion criteria provided
Method: literature only
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MEVALONIC ACIDURIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032943.8
First in ClinVar: Apr 04, 2013 Last updated: Jun 10, 2022 |
Comment on evidence:
Hyper-IgD Syndrome In 2 patients with the hyper-IgD syndrome (HIDS; 260920), Houten et al. (1999) found the V377I mutation (251170.0002) in compound heterozygous state with … (more)
Hyper-IgD Syndrome In 2 patients with the hyper-IgD syndrome (HIDS; 260920), Houten et al. (1999) found the V377I mutation (251170.0002) in compound heterozygous state with a his20-to-pro (H20P) mutation. Mevalonic Aciduria In a patient with mild mevalonic aciduria (MEVA; 610377), Houten et al. (1999) found compound heterozygosity for an A-to-C transversion at nucleotide 59, resulting in a histidine-to-proline substitution at codon 20. The other mutation was a G-to-A transition at nucleotide 1000, resulting in an ala334-to-thr (A334T; 251170.0006) substitution. The patient presented at 6 years of age with cerebellar ataxia, hypotonia, and elevated creatine kinase activity and was still alive at 20 years of age. Nuclear magnetic resonance and computed tomography of the brain revealed cerebellar hypoplasia and an enlarged fourth ventricle. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954581.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001976203.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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Hyperimmunoglobulin D with periodic fever
Affected status: not provided
Allele origin:
not provided
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Unité médicale des maladies autoinflammatoires, CHRU Montpellier
Accession: SCV000115955.1
First in ClinVar: Mar 06, 2014 Last updated: Mar 06, 2014
Comment:
also involved in OMIM 25117
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Defective protein prenylation is a diagnostic biomarker of mevalonate kinase deficiency. | Munoz MA | The Journal of allergy and clinical immunology | 2017 | PMID: 28501347 |
The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry. | Ter Haar NM | Arthritis & rheumatology (Hoboken, N.J.) | 2016 | PMID: 27213830 |
Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. | Mandey SH | Human mutation | 2006 | PMID: 16835861 |
MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever. | D'Osualdo A | European journal of human genetics : EJHG | 2005 | PMID: 15536479 |
Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. | Cuisset L | European journal of human genetics : EJHG | 2001 | PMID: 11313769 |
Molecular basis of classical mevalonic aciduria and the hyperimmunoglobulinaemia D and periodic fever syndrome: high frequency of 3 mutations in the mevalonate kinase gene. | Houten SM | Journal of inherited metabolic disease | 2000 | PMID: 10896296 |
Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis. | Houten SM | Human molecular genetics | 1999 | PMID: 10401001 |
Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. | Houten SM | Nature genetics | 1999 | PMID: 10369261 |
Text-mined citations for rs104895295 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.