VCV000011930.11 - ClinVar

NM_000431.4(MVK):c.1000G>A (p.Ala334Thr)

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.

(6)

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

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.1000G>A (p.Ala334Thr)

Variation ID: 11930 Accession: VCV000011930.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.11 12: 109595142 (GRCh38) [ NCBI UCSC ] 12: 110032947 (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	Feb 28, 2024	Jan 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000431.4:c.1000G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000422.1:p.Ala334Thr	missense
NM_001114185.3:c.1000G>A	NP_001107657.1:p.Ala334Thr	missense
NM_001301182.2:c.844G>A	NP_001288111.1:p.Ala282Thr	missense
NC_000012.12:g.109595142G>A
NC_000012.11:g.110032947G>A
NG_007702.1:g.26448G>A
LRG_156:g.26448G>A
LRG_156t1:c.1000G>A	LRG_156p1:p.Ala334Thr
	Q03426:p.Ala334Thr

... more HGVS ... less HGVS

Protein change

A334T, A282T

Other names

Canonical SPDI

NC_000012.12:109595141: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) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00010

Exome Aggregation Consortium (ExAC) 0.00014

Links

ClinGen: CA121778 UniProtKB: Q03426#VAR_004026 OMIM: 251170.0006 dbSNP: rs104895317 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 (2)	no assertion criteria provided	Dec 1, 2013	RCV000074422.26
Mevalonic aciduria	Pathogenic (1)	no assertion criteria provided	Dec 1, 2013	RCV000012706.30
Hyperimmunoglobulin D with periodic fever Mevalonic aciduria Porokeratosis 3, disseminated superficial actinic type	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 3, 2024	RCV000688831.7
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 30, 2022	RCV003114187.3

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.
Pathogenic (Apr 30, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV003800245.1 First in ClinVar: Feb 13, 2023 Last updated: Feb 13, 2023	Comment: The MVK c.1000G>A; p.Ala334Thr variant (rs104895317) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with mevalonate kinase … (more) The MVK c.1000G>A; p.Ala334Thr variant (rs104895317) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with mevalonate kinase deficiency (Balgobind 2005, Brennenstuhl 2021, Gattorno 2009, Hinson 1997, Prietsch 2003, Siemiatkowska 2013). This variant is found in the non-Finnish European population with an allele frequency of 0.02% (22/128940 alleles) in the Genome Aggregation Database. The alanine at codon 334 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.862). Consistent with these predictions, functional studies indicate the variant protein has reduced enzymatic activity in vitro and in patient cells (Hinson 1997). Based on available information, this variant is considered to be pathogenic. References: Balgobind B et al. Retinitis pigmentosa in mevalonate kinase deficiency. J Inherit Metab Dis. 2005;28(6):1143-5. PMID: 16435210. Brennenstuhl et al. Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria. J Inherit Metab Dis. 2021 Sep;44(5):1272-1287. PMID: 34145613 Gattorno M et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009 Oct;124(4):e721-8. PMID: 1978643 Hinson DD et al. Identification of an active site alanine in mevalonate kinase through characterization of a novel mutation in mevalonate kinase deficiency. J Biol Chem. 1997 Oct 17;272(42):26756-60. PMID: 9334262. Prietsch V et al. Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum. Pediatrics. 2003 Feb;111(2):258-61. PMID: 12563048. Siemiatkowska AM et al. Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa. Ophthalmology. 2013 Dec;120(12):2697-2705. PMID: 24084495. (less)
Pathogenic (Jan 03, 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: SCV000816455.5 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (8) PubMed: 28492532‚ 9334262‚ 10401001‚ 12563048‚ 16435210‚ 19786432‚ 24084495‚ 28095071 Comment: This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the MVK protein (p.Ala334Thr). … (more) This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the MVK protein (p.Ala334Thr). This variant is present in population databases (rs104895317, gnomAD 0.02%). This missense change has been observed in individual(s) with mevalonate kinase deficiency and retinitis pigmentosa (PMID: 9334262, 10401001, 12563048, 16435210, 19786432, 24084495, 28095071). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11930). 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%. Experimental studies have shown that this missense change affects MVK function (PMID: 9334262). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 13, 2022)	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: SCV002786434.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 01, 2013)	no assertion criteria provided Method: literature only	MEVALONIC ACIDURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032941.9 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2022	Publications: PubMed (5) PubMed: 8386351‚ 12563048‚ 10401001‚ 16435210‚ 24084495 Comment on evidence: Mevalonic Aciduria In a 15-year-old girl and her 14-year-old brother with mevalonic aciduria (MEVA; 610377), previously studied by Hoffmann et al. (1993), in whom the … (more) Mevalonic Aciduria In a 15-year-old girl and her 14-year-old brother with mevalonic aciduria (MEVA; 610377), previously studied by Hoffmann et al. (1993), in whom the phenotype had gradually shifted from febrile crises to ataxia and who also exhibited nuclear cataract and retinal dystrophy, Prietsch et al. (2003) identified homozygosity for an A334T missense mutation in the MVK gene. In an unrelated 6-year-old-boy with mevalonic aciduria, who had cerebellar ataxia but no febrile crises or elevated IgD, and who also showed retinal dystrophy, Prietsch et al. (2003) identified compound heterozygosity for the A334T mutation and a 1-bp insertion (72insT; 251170.0016). For discussion of the ala334-to-thr (A334T) mutation in the MVK gene that was found in compound heterozygous state in a patient with mild mevalonic aciduria by Houten et al. (1999), see 251170.0003. Hyper-IgD Syndrome In a 5-year-old boy with hyper-IgD syndrome (HIDS; 260920) and retinitis pigmentosa, Balgobind et al. (2005) identified compound heterozygosity for the A334T mutation and a 1-bp insertion (421insG; 251170.0017) in the MVK gene. In a Dutch brother and sister with retinitis pigmentosa and a history of episodic fevers in childhood, Siemiatkowska et al. (2013) identified compound heterozygosity for the A334T and I268T (251170.0004) missense mutations in the MVK gene, which segregated with disease in the family and were not found in 174 Dutch controls. Both sibs had elevated IgD levels and severely reduced MVK activity. Analysis of the MVK gene in 769 additional RP patients without a genetic diagnosis revealed a 61-year-old Dutch man who was homozygous for the A334T mutation. He also had ischemic heart disease and renal failure; his IgD level was normal, but MVK activity was only 0.22% of control. Siemiatkowska et al. (2013) noted that all 3 patients had mild systemic symptoms despite markedly reduced activity of MVK, and suggested that differences in genetic background or environmental factors might play a role in disease manifestations. (less)
Pathogenic (Dec 01, 2013)	no assertion criteria provided Method: literature only	HYPER-IgD SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000108438.8 First in ClinVar: Nov 28, 2013 Last updated: Jun 09, 2022	Publications: PubMed (5) PubMed: 8386351‚ 12563048‚ 10401001‚ 16435210‚ 24084495 Comment on evidence: Mevalonic Aciduria In a 15-year-old girl and her 14-year-old brother with mevalonic aciduria (MEVA; 610377), previously studied by Hoffmann et al. (1993), in whom the … (more) Mevalonic Aciduria In a 15-year-old girl and her 14-year-old brother with mevalonic aciduria (MEVA; 610377), previously studied by Hoffmann et al. (1993), in whom the phenotype had gradually shifted from febrile crises to ataxia and who also exhibited nuclear cataract and retinal dystrophy, Prietsch et al. (2003) identified homozygosity for an A334T missense mutation in the MVK gene. In an unrelated 6-year-old-boy with mevalonic aciduria, who had cerebellar ataxia but no febrile crises or elevated IgD, and who also showed retinal dystrophy, Prietsch et al. (2003) identified compound heterozygosity for the A334T mutation and a 1-bp insertion (72insT; 251170.0016). For discussion of the ala334-to-thr (A334T) mutation in the MVK gene that was found in compound heterozygous state in a patient with mild mevalonic aciduria by Houten et al. (1999), see 251170.0003. Hyper-IgD Syndrome In a 5-year-old boy with hyper-IgD syndrome (HIDS; 260920) and retinitis pigmentosa, Balgobind et al. (2005) identified compound heterozygosity for the A334T mutation and a 1-bp insertion (421insG; 251170.0017) in the MVK gene. In a Dutch brother and sister with retinitis pigmentosa and a history of episodic fevers in childhood, Siemiatkowska et al. (2013) identified compound heterozygosity for the A334T and I268T (251170.0004) missense mutations in the MVK gene, which segregated with disease in the family and were not found in 174 Dutch controls. Both sibs had elevated IgD levels and severely reduced MVK activity. Analysis of the MVK gene in 769 additional RP patients without a genetic diagnosis revealed a 61-year-old Dutch man who was homozygous for the A334T mutation. He also had ischemic heart disease and renal failure; his IgD level was normal, but MVK activity was only 0.22% of control. Siemiatkowska et al. (2013) noted that all 3 patients had mild systemic symptoms despite markedly reduced activity of MVK, and suggested that differences in genetic background or environmental factors might play a role in disease manifestations. (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: SCV000115913.1 First in ClinVar: Mar 06, 2014 Last updated: Mar 06, 2014 Comment: also involved in OMIM 25117

Comment:

The MVK c.1000G>A; p.Ala334Thr variant (rs104895317) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with mevalonate kinase deficiency (Balgobind 2005, Brennenstuhl 2021, Gattorno 2009, Hinson 1997, Prietsch 2003, Siemiatkowska 2013). This variant is found in the non-Finnish European population with an allele frequency of 0.02% (22/128940 alleles) in the Genome Aggregation Database. The alanine at codon 334 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.862). Consistent with these predictions, functional studies indicate the variant protein has reduced enzymatic activity in vitro and in patient cells (Hinson 1997). Based on available information, this variant is considered to be pathogenic. References: Balgobind B et al. Retinitis pigmentosa in mevalonate kinase deficiency. J Inherit Metab Dis. 2005;28(6):1143-5. PMID: 16435210. Brennenstuhl et al. Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria. J Inherit Metab Dis. 2021 Sep;44(5):1272-1287. PMID: 34145613 Gattorno M et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009 Oct;124(4):e721-8. PMID: 1978643 Hinson DD et al. Identification of an active site alanine in mevalonate kinase through characterization of a novel mutation in mevalonate kinase deficiency. J Biol Chem. 1997 Oct 17;272(42):26756-60. PMID: 9334262. Prietsch V et al. Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum. Pediatrics. 2003 Feb;111(2):258-61. PMID: 12563048. Siemiatkowska AM et al. Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa. Ophthalmology. 2013 Dec;120(12):2697-2705. PMID: 24084495.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the MVK protein (p.Ala334Thr). This variant is present in population databases (rs104895317, gnomAD 0.02%). This missense change has been observed in individual(s) with mevalonate kinase deficiency and retinitis pigmentosa (PMID: 9334262, 10401001, 12563048, 16435210, 19786432, 24084495, 28095071). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11930). 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%. Experimental studies have shown that this missense change affects MVK function (PMID: 9334262). For these reasons, this variant has been 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
Mevalonate kinase deficiency associated with ataxia and retinitis pigmentosa in two brothers with MVK gene mutations.	Kellner U	Ophthalmic genetics	2017	PMID: 28095071
Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa.	Siemiatkowska AM	Ophthalmology	2013	PMID: 24084495
Differentiating PFAPA syndrome from monogenic periodic fevers.	Gattorno M	Pediatrics	2009	PMID: 19786432
Retinitis pigmentosa in mevalonate kinase deficiency.	Balgobind B	Journal of inherited metabolic disease	2005	PMID: 16435210
Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum.	Prietsch V	Pediatrics	2003	PMID: 12563048
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
Identification of an active site alanine in mevalonate kinase through characterization of a novel mutation in mevalonate kinase deficiency.	Hinson DD	The Journal of biological chemistry	1997	PMID: 9334262
Clinical and biochemical phenotype in 11 patients with mevalonic aciduria.	Hoffmann GF	Pediatrics	1993	PMID: 8386351

Text-mined citations for rs104895317 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000431.4(MVK):c.1000G>A (p.Ala334Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104895317 ...