12-109581523-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001414515.1(MVK):c.-83C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MVK
NM_001414515.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 3.43

Variant links:

Genes affected

MVK (HGNC:7530): (mevalonate kinase) This gene encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is a key intermediate, and mevalonate kinase a key early enzyme, in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene results in mevalonic aciduria, a disease characterized psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MVK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

PP5

Variant 12-109581523-C-T is Pathogenic according to our data. Variant chr12-109581523-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581523-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVK	NM_000431.4 link	c.500C>T	p.Pro167Leu	missense_variant	Exon 5 of 11	ENST00000228510.8	NP_000422.1	Q03426B2RDU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8 link	c.500C>T	p.Pro167Leu	missense_variant	Exon 5 of 11	1	NM_000431.4	ENSP00000228510.3		Q03426

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251380

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Dec 23, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The P167L likely pathogenic variant, also reported as P165L, in the MVK gene has been observed previously in patients with Hyper IgD syndrome including in both the homozygous and compound heterozygous states (Simon et al., 2004; de Wolff et al., 2009; Cuisset et al., 2001; Drenth et al., 1999). It was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. P167L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Although this substitution occurs at a position that is not conserved, in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (P165L, N166I, G171R) have been reported in the Human Gene Mutation Database in association with MVK-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hyperimmunoglobulin D with periodic fever

Pathogenic:2Other:1

Jun 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MVK c.500C>T (p.Pro167Leu), also referred to as c.591C>T (P165L) in the literature, results in a non-conservative amino acid change located in the GHMP kinase N-terminal domain (IPR006204) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251380 control chromosomes. c.500C>T has been reported in the literature in at least one homozygote and multiple compound heterozygous individuals affected with Hyper-IgD syndrome (HIDS)/mevalonate kinase deficiency (e.g. Drenth_1999, Cuisset_2001, Simon_2006, Van Gorp_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11313769, 10369262, 16234278, 32312770). ClinVar contains an entry for this variant (Variation ID: 39725). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria

Pathogenic:1

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 39725). This missense change has been observed in individual(s) with hyper IgD syndrome (PMID: 10369262, 11313769). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs104895300, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 167 of the MVK protein (p.Pro167Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

.;D;D;D

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

D;T;.;T

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.3

.;.;M;M

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.7

D;D;D;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0030

D;T;T;.

Sift4G

Uncertain

0.0080

D;T;T;T

Polyphen

0.99

.;.;D;D

Vest4

0.73, 0.74

MVP

0.95

MPC

0.99

ClinPred

0.93

GERP RS

4.2

Varity_R

0.36

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over