NM_000431.4(MVK):c.494C>T (p.Pro165Leu) AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Apr 19, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001219913.2

Allele description [Variation Report for NM_000431.4(MVK):c.494C>T (p.Pro165Leu)]

NM_000431.4(MVK):c.494C>T (p.Pro165Leu)

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.494C>T (p.Pro165Leu)
HGVS:
  • NC_000012.12:g.109581517C>T
  • NG_007702.1:g.12823C>T
  • NM_000431.4:c.494C>TMANE SELECT
  • NM_001114185.3:c.494C>T
  • NM_001301182.2:c.371+1571C>T
  • NP_000422.1:p.Pro165Leu
  • NP_001107657.1:p.Pro165Leu
  • LRG_156t1:c.494C>T
  • LRG_156:g.12823C>T
  • LRG_156p1:p.Pro165Leu
  • NC_000012.11:g.110019322C>T
  • NM_000431.3:c.494C>T
Protein change:
P165L; PRO165LEU
Links:
OMIM: 251170.0005; dbSNP: rs121917790
NCBI 1000 Genomes Browser:
rs121917790
Molecular consequence:
  • NM_001301182.2:c.371+1571C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000431.4:c.494C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001114185.3:c.494C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Mevalonic aciduria (MEVA)
Synonyms:
Mevalonate kinase deficiency
Identifiers:
MedGen: C1959626; Orphanet: 29; OMIM: 610377
Name:
Porokeratosis 3, disseminated superficial actinic type (DSAP1)
Synonyms:
Porokeratosis, disseminated superficial actinic 1; POROKERATOSIS 3, MULTIPLE TYPES; POROKERATOSIS 3, MIBELLI TYPE
Identifiers:
MONDO: MONDO:0008293; MedGen: C1867981; OMIM: 175900
Name:
Hyperimmunoglobulin D with periodic fever (HIDS)
Synonyms:
Hyperimmunoglobulinemia D and periodic fever syndrome; Periodic fever Dutch type; Hyperimmunoglobulinemia D
Identifiers:
MONDO: MONDO:0009849; MedGen: C0398691; Orphanet: 343; OMIM: 260920

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001391878Invitaecriteria provided, single submitter
Likely pathogenic
(Apr 19, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group.

Drenth JP, Cuisset L, Grateau G, Vasseur C, van de Velde-Visser SD, de Jong JG, Beckmann JS, van der Meer JW, Delpech M.

Nat Genet. 1999 Jun;22(2):178-81.

PubMed [citation]
PMID:
10369262

A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry.

Papa R, Doglio M, Lachmann HJ, Ozen S, Frenkel J, Simon A, Neven B, Kuemmerle-Deschner J, Ozgodan H, Caorsi R, Federici S, Finetti M, Trachana M, Brunner J, Bezrodnik L, Pinedo Gago MC, Maggio MC, Tsitsami E, Al Suwairi W, Espada G, Shcherbina A, Aksu G, et al.

Orphanet J Rare Dis. 2017 Oct 18;12(1):167. doi: 10.1186/s13023-017-0720-3.

PubMed [citation]
PMID:
29047407
PMCID:
PMC5648458
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001391878.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces proline with leucine at codon 165 of the MVK protein (p.Pro165Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features consistent with hyper IgD syndrome or mevalonate kinase deficiency (PMID: 10369262, 29047407). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 11933). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this allele has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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