VCV000097612.38 - ClinVar

NM_000431.4(MVK):c.709A>T (p.Thr237Ser)

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.

(7)

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.709A>T (p.Thr237Ser)

Variation ID: 97612 Accession: VCV000097612.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.11 12: 109590802 (GRCh38) [ NCBI UCSC ] 12: 110028607 (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	Feb 20, 2014	Oct 20, 2024	Dec 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000431.4:c.709A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000422.1:p.Thr237Ser	missense
NM_001114185.3:c.709A>T	NP_001107657.1:p.Thr237Ser	missense
NM_001301182.2:c.553A>T	NP_001288111.1:p.Thr185Ser	missense
NC_000012.12:g.109590802A>T
NC_000012.11:g.110028607A>T
NG_007702.1:g.22108A>T
LRG_156:g.22108A>T
LRG_156t1:c.709A>T

... more HGVS ... less HGVS

Protein change

T237S, T185S

Other names

Canonical SPDI

NC_000012.12:109590801:A:T

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) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA149879 dbSNP: rs104895366 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	Likely pathogenic (2)	criteria provided, single submitter	Oct 21, 2022	RCV000083864.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 4, 2021	RCV000480950.25
Hyperimmunoglobulin D with periodic fever Mevalonic aciduria Porokeratosis 3, disseminated superficial actinic type	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 5, 2023	RCV001381669.7
Mevalonic aciduria	Pathogenic (1)	criteria provided, single submitter	Dec 21, 2023	RCV004593989.1

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 (Oct 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hyperimmunoglobulin D with periodic fever Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003808088.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PP3 supporting Number of individuals with the variant: 1 Clinical Features: Abdominal pain (present) , Recurrent fever (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Apr 01, 2019)	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: SCV001246719.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Mar 09, 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: SCV002776185.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Oct 04, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568224.6 First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a significantly lowered MK enzyme activity (Rolland et al., 2005; Mandey et al., 2006); Not observed at significant frequency in large … (more) Published functional studies demonstrate a significantly lowered MK enzyme activity (Rolland et al., 2005; Mandey et al., 2006); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 25525159, 21708801, 16835861, 16435209, 21225694, 22038276, 22566169, 27213830, 21124859, 28814775, 31096039, 31589614) (less)
Pathogenic (Dec 05, 2023)	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: SCV001580161.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 16197847‚ 16835861‚ 21708801‚ 28814775‚ 31096039 Comment: This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 237 of the MVK protein (p.Thr237Ser). … (more) This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 237 of the MVK protein (p.Thr237Ser). This variant is present in population databases (rs104895366, gnomAD 0.002%). This missense change has been observed in individual(s) with Mevalonate kinase deficiency (PMID: 16197847, 16835861, 21708801, 28814775, 31096039). ClinVar contains an entry for this variant (Variation ID: 97612). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mevalonic aciduria (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005085978.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 27012807‚ 31096039‚ 32822427 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mevalonic aciduria (MIM#610377). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial variability has been reported (PMID: 32822427). In addition, this gene may be associated with a spectrum of disease, including severe perinatal presentations with hydrops (PMID: 27012807). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 5 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with mevalonate kinase deficiency (ClinVar; PMID: 31096039). (SP) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000431.2:c.1139A>G; p.(His380Arg)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (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: SCV000115969.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: also involved in OMIM 25117

Comment:

Published functional studies demonstrate a significantly lowered MK enzyme activity (Rolland et al., 2005; Mandey et al., 2006); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 25525159, 21708801, 16835861, 16435209, 21225694, 22038276, 22566169, 27213830, 21124859, 28814775, 31096039, 31589614)

Comment:

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 237 of the MVK protein (p.Thr237Ser). This variant is present in population databases (rs104895366, gnomAD 0.002%). This missense change has been observed in individual(s) with Mevalonate kinase deficiency (PMID: 16197847, 16835861, 21708801, 28814775, 31096039). ClinVar contains an entry for this variant (Variation ID: 97612). 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%. For these reasons, this variant has been classified as Pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mevalonic aciduria (MIM#610377). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial variability has been reported (PMID: 32822427). In addition, this gene may be associated with a spectrum of disease, including severe perinatal presentations with hydrops (PMID: 27012807). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 5 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with mevalonate kinase deficiency (ClinVar; PMID: 31096039). (SP) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000431.2:c.1139A>G; p.(His380Arg)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome.	Govindaraj GM	PloS one	2020	PMID: 32822427
When neonatal inflammation does not mean infection: an early-onset mevalonate kinase deficiency with interstitial lung disease.	Pietrasanta C	Clinical immunology (Orlando, Fla.)	2019	PMID: 31096039
Mutational profile of rare variants in inflammasome-related genes in Behçet disease: A Next Generation Sequencing approach.	Burillo-Sanz S	Scientific reports	2017	PMID: 28814775
Perinatal manifestation of mevalonate kinase deficiency and efficacy of anakinra.	Peciuliene S	Pediatric rheumatology online journal	2016	PMID: 27012807
Mevalonate kinase deficiency: a survey of 50 patients.	Bader-Meunier B	Pediatrics	2011	PMID: 21708801
Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency.	Mandey SH	Human mutation	2006	PMID: 16835861
[Periodic fever: the first Portuguese case-report of hyper-IgD syndrome (HIDS)].	Abreu TT	Acta medica portuguesa	2004	PMID: 16197847

Text-mined citations for rs104895366 ...

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.709A>T (p.Thr237Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104895366 ...