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NM_000431.4(MVK):c.803T>C (p.Ile268Thr) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 25, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002512988.2

Allele description

NM_000431.4(MVK):c.803T>C (p.Ile268Thr)

Gene:
MVK:mevalonate kinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q24.11
Genomic location:
Preferred name:
NM_000431.4(MVK):c.803T>C (p.Ile268Thr)
HGVS:
  • NC_000012.12:g.109591275T>C
  • NG_007702.1:g.22581T>C
  • NM_000431.4:c.803T>CMANE SELECT
  • NM_001114185.3:c.803T>C
  • NM_001301182.2:c.647T>C
  • NP_000422.1:p.Ile268Thr
  • NP_001107657.1:p.Ile268Thr
  • NP_001288111.1:p.Ile216Thr
  • LRG_156t1:c.803T>C
  • LRG_156:g.22581T>C
  • LRG_156p1:p.Ile268Thr
  • NC_000012.11:g.110029080T>C
  • NM_000431.1:c.803T>C
  • NM_000431.2:c.803T>C
  • NM_000431.3:c.803T>C
  • NM_001114185.1:c.803T>C
  • NM_001301182.1:c.647T>C
  • Q03426:p.Ile268Thr
Protein change:
I216T; ILE268THR
Links:
UniProtKB: Q03426#VAR_004024; OMIM: 251170.0004; dbSNP: rs104895304
NCBI 1000 Genomes Browser:
rs104895304
Molecular consequence:
  • NM_000431.4:c.803T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001114185.3:c.803T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001301182.2:c.647T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003685036Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Pathogenic
(Mar 25, 2022) 		germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Perinatal onset mevalonate kinase deficiency.

Steiner LA, Ehrenkranz RA, Peterec SM, Steiner RD, Reyes-Múgica M, Gallagher PG.

Pediatr Dev Pathol. 2011 Jul-Aug;14(4):301-6. doi: 10.2350/11-02-0985-OA.1. Epub 2011 Mar 22.

PubMed [citation]
PMID:
21425920

Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria.

Brennenstuhl H, Nashawi M, Schröter J, Baronio F, Beedgen L, Gleich F, Jeltsch K, von Landenberg C, Martini S, Simon A, Thiel C, Tsiakas K, Opladen T, Kölker S, Hoffmann GF, Haas D; Unified Registry for Inherited Metabolic Disorders (U-IMD) Consortium and the European Registry for Hereditary Metabolic Disorders (MetabERN)..

J Inherit Metab Dis. 2021 Sep;44(5):1272-1287. doi: 10.1002/jimd.12412. Epub 2021 Jun 28.

PubMed [citation]
PMID:
34145613
See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV003685036.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (14)

Description

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). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Apr 20, 2024