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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 19, 2019
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:: RCV001219913.7

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)
Identifiers:: MONDO: MONDO:0012481; 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; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009849; MedGen: C0398691; Orphanet: 343; OMIM: 260920

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001391878	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 19, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10369262, 29047407, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001391878

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 19, 2019)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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, SCV001391878.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this allele has been classified as Likely Pathogenic. 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. 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). This variant is not present in population databases (ExAC no frequency). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 5, 2024

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