VCV000039726.40 - ClinVar

NM_000431.4(MVK):c.604G>A (p.Gly202Arg)

Germline

Classification

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.

(10)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000431.4(MVK):c.604G>A (p.Gly202Arg)

Variation ID: 39726 Accession: VCV000039726.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.11 12: 109586098 (GRCh38) [ NCBI UCSC ] 12: 110023903 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 26, 2024	Aug 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000431.4:c.604G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000422.1:p.Gly202Arg	missense
NM_001114185.3:c.604G>A	NP_001107657.1:p.Gly202Arg	missense
NM_001301182.2:c.448G>A	NP_001288111.1:p.Gly150Arg	missense
NC_000012.12:g.109586098G>A
NC_000012.11:g.110023903G>A
NG_007702.1:g.17404G>A
LRG_156:g.17404G>A
LRG_156t1:c.604G>A
	Q03426:p.Gly202Arg

... more HGVS ... less HGVS

Protein change

G202R, G150R

Other names

Canonical SPDI

NC_000012.12:109586097:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA130490 UniProtKB: Q03426#VAR_010962 OMIM: 251170.0010 dbSNP: rs104895301 VarSome

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
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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 Help 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.
MVK		-	-	GRCh38 GRCh37	658	753

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 Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hyperimmunoglobulin D with periodic fever	Pathogenic (3)	criteria provided, single submitter	Aug 16, 2024	RCV000032938.32
Mevalonic aciduria	Pathogenic (2)	criteria provided, single submitter	Mar 23, 2020	RCV000032939.34
Porokeratosis 3, disseminated superficial actinic type	Pathogenic (1)	no assertion criteria provided	Oct 1, 2012	RCV000032940.22
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 7, 2022	RCV001090935.26
Hyperimmunoglobulin D with periodic fever Mevalonic aciduria Porokeratosis 3, disseminated superficial actinic type	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV002496494.5

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 Help 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 Help 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.
Likely pathogenic (Mar 07, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001797086.3 First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); 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: 24008101, 22566169, 24131530, 15324368, 26794421, 27422687, 21274502, 16011988, 16835861, 11313769, 19543954, 34188266, 33168400, 33619735, 22983302) (less)
Likely pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003441295.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 11313769‚ 22566169‚ 22983302‚ 26202976‚ 33168400 Comment: This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 202 of the MVK protein (p.Gly202Arg). … (more) This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 202 of the MVK protein (p.Gly202Arg). This variant is present in population databases (rs104895301, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive mevalonate kinase deficiency (PMID: 11313769, 22566169; Invitae). This variant has been reported in individual(s) with autosomal dominant porokeratosis (PMID: 22983302, 26202976, 33168400); however, the role of the variant in this condition is currently unclear. This variant is also known as c.695G>A. ClinVar contains an entry for this variant (Variation ID: 39726). 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 with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Pathogenic (Mar 23, 2020)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Mevalonic aciduria (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001429936.1 First in ClinVar: Aug 21, 2020 Last updated: Aug 21, 2020	Clinical Features: Cerebral atrophy (present) , Abnormal visual fixation (present) , Wide nasal bridge (present) , Narrow palpebral fissure (present) , Limb hypertonia (present) , Motor deterioration … (more) Cerebral atrophy (present) , Abnormal visual fixation (present) , Wide nasal bridge (present) , Narrow palpebral fissure (present) , Limb hypertonia (present) , Motor deterioration (present) , Abnormal optic nerve morphology (present) , Global developmental delay (present) , Short nasal bridge (present) , Abnormal basal ganglia morphology (present) , Poor head control (present) , Leukodystrophy (present) , Microcephaly (present) , Uplifted earlobe (present) , Epicanthus inversus (present) , Delayed CNS myelination (present) , Axial hypotonia (present) (less) Sex: male Tissue: blood
Pathogenic (Oct 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246718.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Aug 16, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hyperimmunoglobulin D with periodic fever Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005380952.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Publications: PubMed (2) PubMed: 11313769‚ 22983302 Comment: Variant summary: MVK c.604G>A (p.Gly202Arg) results in a non-conservative amino acid change located in the GHMP kinase N-terminal domain (IPR006204) of the encoded protein sequence. … (more) Variant summary: MVK c.604G>A (p.Gly202Arg) results in a non-conservative amino acid change located in the GHMP kinase N-terminal domain (IPR006204) of 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 4e-06 in 251388 control chromosomes. c.604G>A has been reported in the literature in compound heterozygous genotype in an individual affected with autosomal recessive Hyper-IgD syndrome and as heterozygous genotype in multiple individuals affected with autosomal dominant Disseminated superficial actinic porokeratosis (Cuisset_2001, Zhang_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11313769, 22983302). ClinVar contains an entry for this variant (Variation ID: 39726). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Nov 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Porokeratosis 3, disseminated superficial actinic type Hyperimmunoglobulin D with periodic fever Mevalonic aciduria Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002807548.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Oct 01, 2012)	no assertion criteria provided Method: literature only	HYPER-IgD SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056710.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2022	Publications: PubMed (3) PubMed: 11313769‚ 16835861‚ 22983302 Comment on evidence: Hyper-IgD Syndrome In a patient with hyper-IgD syndrome (HIDS; 260920), Cuisset et al. (2001) identified compound heterozygosity for 2 mutations in the MVK gene: a … (more) Hyper-IgD Syndrome In a patient with hyper-IgD syndrome (HIDS; 260920), Cuisset et al. (2001) identified compound heterozygosity for 2 mutations in the MVK gene: a gly202-to-arg (G202R) substitution and a pro167-to-leu (P167L; 251170.0011) substitution. The patient died of Staphylococcal pneumonia at age 30 years, but she did not have any attacks in the 18 months preceding her death. MVK activity was 1.8% of controls. Cuisset et al. (2001) stated that the G202R mutation resulted from a 695G-A transition in exon 5. Mevalonic Aciduria Mandey et al. (2006) reported that a patient with mevalonic aciduria (MEVA; 610377) carried the G202R mutation, which resulted from a 604G-A transition in exon 6; it was not clear from this paper whether the patient was homozygous for the mutation or carried a second MVK mutation on the other allele. Porokeratosis 3 Zhang et al. (2012) identified heterozygosity for the G202R mutation in affected members of 6 unrelated Chinese families with disseminated superficial actinic porokeratosis (POROK3; 175900). The mutation was also found in a patient with sporadic disease and was not found in 676 control individuals. Two members of 1 family with this mutation had markedly different phenotypes: 1 had typical features of the disorder, whereas the other had an extremely mild phenotype that could not be readily diagnosed. Zhang et al. (2012) noted that this mutation had previously been identified in patients with hyper-IgD syndrome and mevalonic aciduria. However, the patients with porokeratosis had no clinical features of either disorder, including normal IgD levels. Although porokeratosis lesions had not been reported in individuals with mevalonic aciduria, some cases with hyper-IgD syndrome can have transient inflammatory skin lesions. In addition, heterozygous parents of patients with recessive MVK mutations do not have features of porokeratosis. This clinical diversity resulting from the same mutation suggests the involvement of additional factors, such as environmental exposure, particularly ultraviolet radiation. (less)
Pathogenic (Oct 01, 2012)	no assertion criteria provided Method: literature only	MEVALONIC ACIDURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056711.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2022	Publications: PubMed (3) PubMed: 11313769‚ 16835861‚ 22983302 Comment on evidence: Hyper-IgD Syndrome In a patient with hyper-IgD syndrome (HIDS; 260920), Cuisset et al. (2001) identified compound heterozygosity for 2 mutations in the MVK gene: a … (more) Hyper-IgD Syndrome In a patient with hyper-IgD syndrome (HIDS; 260920), Cuisset et al. (2001) identified compound heterozygosity for 2 mutations in the MVK gene: a gly202-to-arg (G202R) substitution and a pro167-to-leu (P167L; 251170.0011) substitution. The patient died of Staphylococcal pneumonia at age 30 years, but she did not have any attacks in the 18 months preceding her death. MVK activity was 1.8% of controls. Cuisset et al. (2001) stated that the G202R mutation resulted from a 695G-A transition in exon 5. Mevalonic Aciduria Mandey et al. (2006) reported that a patient with mevalonic aciduria (MEVA; 610377) carried the G202R mutation, which resulted from a 604G-A transition in exon 6; it was not clear from this paper whether the patient was homozygous for the mutation or carried a second MVK mutation on the other allele. Porokeratosis 3 Zhang et al. (2012) identified heterozygosity for the G202R mutation in affected members of 6 unrelated Chinese families with disseminated superficial actinic porokeratosis (POROK3; 175900). The mutation was also found in a patient with sporadic disease and was not found in 676 control individuals. Two members of 1 family with this mutation had markedly different phenotypes: 1 had typical features of the disorder, whereas the other had an extremely mild phenotype that could not be readily diagnosed. Zhang et al. (2012) noted that this mutation had previously been identified in patients with hyper-IgD syndrome and mevalonic aciduria. However, the patients with porokeratosis had no clinical features of either disorder, including normal IgD levels. Although porokeratosis lesions had not been reported in individuals with mevalonic aciduria, some cases with hyper-IgD syndrome can have transient inflammatory skin lesions. In addition, heterozygous parents of patients with recessive MVK mutations do not have features of porokeratosis. This clinical diversity resulting from the same mutation suggests the involvement of additional factors, such as environmental exposure, particularly ultraviolet radiation. (less)
Pathogenic (Oct 01, 2012)	no assertion criteria provided Method: literature only	POROKERATOSIS 3, DISSEMINATED SUPERFICIAL ACTINIC TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056712.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2022	Publications: PubMed (3) PubMed: 11313769‚ 16835861‚ 22983302 Comment on evidence: Hyper-IgD Syndrome In a patient with hyper-IgD syndrome (HIDS; 260920), Cuisset et al. (2001) identified compound heterozygosity for 2 mutations in the MVK gene: a … (more) Hyper-IgD Syndrome In a patient with hyper-IgD syndrome (HIDS; 260920), Cuisset et al. (2001) identified compound heterozygosity for 2 mutations in the MVK gene: a gly202-to-arg (G202R) substitution and a pro167-to-leu (P167L; 251170.0011) substitution. The patient died of Staphylococcal pneumonia at age 30 years, but she did not have any attacks in the 18 months preceding her death. MVK activity was 1.8% of controls. Cuisset et al. (2001) stated that the G202R mutation resulted from a 695G-A transition in exon 5. Mevalonic Aciduria Mandey et al. (2006) reported that a patient with mevalonic aciduria (MEVA; 610377) carried the G202R mutation, which resulted from a 604G-A transition in exon 6; it was not clear from this paper whether the patient was homozygous for the mutation or carried a second MVK mutation on the other allele. Porokeratosis 3 Zhang et al. (2012) identified heterozygosity for the G202R mutation in affected members of 6 unrelated Chinese families with disseminated superficial actinic porokeratosis (POROK3; 175900). The mutation was also found in a patient with sporadic disease and was not found in 676 control individuals. Two members of 1 family with this mutation had markedly different phenotypes: 1 had typical features of the disorder, whereas the other had an extremely mild phenotype that could not be readily diagnosed. Zhang et al. (2012) noted that this mutation had previously been identified in patients with hyper-IgD syndrome and mevalonic aciduria. However, the patients with porokeratosis had no clinical features of either disorder, including normal IgD levels. Although porokeratosis lesions had not been reported in individuals with mevalonic aciduria, some cases with hyper-IgD syndrome can have transient inflammatory skin lesions. In addition, heterozygous parents of patients with recessive MVK mutations do not have features of porokeratosis. This clinical diversity resulting from the same mutation suggests the involvement of additional factors, such as environmental exposure, particularly ultraviolet radiation. (less)
not provided (-)	no classification provided Method: not provided	Hyperimmunoglobulin D with periodic fever Affected status: not provided Allele origin: unknown	Unité médicale des maladies autoinflammatoires, CHRU Montpellier Accession: SCV000115956.1 First in ClinVar: Mar 06, 2014 Last updated: Mar 06, 2014 Comment: also involved in OMIM 25117

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); 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: 24008101, 22566169, 24131530, 15324368, 26794421, 27422687, 21274502, 16011988, 16835861, 11313769, 19543954, 34188266, 33168400, 33619735, 22983302)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 202 of the MVK protein (p.Gly202Arg). This variant is present in population databases (rs104895301, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive mevalonate kinase deficiency (PMID: 11313769, 22566169; Invitae). This variant has been reported in individual(s) with autosomal dominant porokeratosis (PMID: 22983302, 26202976, 33168400); however, the role of the variant in this condition is currently unclear. This variant is also known as c.695G>A. ClinVar contains an entry for this variant (Variation ID: 39726). 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 with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

Variant summary: MVK c.604G>A (p.Gly202Arg) results in a non-conservative amino acid change located in the GHMP kinase N-terminal domain (IPR006204) of 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 4e-06 in 251388 control chromosomes. c.604G>A has been reported in the literature in compound heterozygous genotype in an individual affected with autosomal recessive Hyper-IgD syndrome and as heterozygous genotype in multiple individuals affected with autosomal dominant Disseminated superficial actinic porokeratosis (Cuisset_2001, Zhang_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11313769, 22983302). ClinVar contains an entry for this variant (Variation ID: 39726). Based on the evidence outlined above, the variant was classified as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Twenty-two novel mutations in a Chinese cohort of 137 patients with porokeratosis were identified using microfluidics (Fluidigm).	Shi W	Journal of dermatological science	2021	PMID: 33168400
Genomic variations of the mevalonate pathway in porokeratosis.	Zhang Z	eLife	2015	PMID: 26202976
Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis.	Zhang SQ	Nature genetics	2012	PMID: 22983302
Hereditary autoinflammatory syndromes: a Brazilian multicenter study.	Jesus AA	Journal of clinical immunology	2012	PMID: 22566169
Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency.	Mandey SH	Human mutation	2006	PMID: 16835861
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

Text-mined citations for rs104895301 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000431.4(MVK):c.604G>A (p.Gly202Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104895301 ...