chr12-109591275-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000431.4(MVK):c.803T>C(p.Ile268Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000192 in 1,613,992 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

MVK
NM_000431.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 4.63

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 14 ACMG points.

PM1

In a helix (size 25) in uniprot entity KIME_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000431.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

PP5

Variant 12-109591275-T-C is Pathogenic according to our data. Variant chr12-109591275-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 11932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109591275-T-C is described in Lovd as [Pathogenic]. Variant chr12-109591275-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVK	NM_000431.4 link	c.803T>C	p.Ile268Thr	missense_variant	Exon 9 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.803T>C	p.Ile268Thr	missense_variant	Exon 9 of 11	1	NM_000431.4	ENSP00000228510.3		Q03426

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000151

AC:

AN:

251464

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000194

AC:

284

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

133

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000235

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000171

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000288

Hom.:

Bravo

AF:

0.000174

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

- -

Aug 19, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In a study of 103 individuals who had a clinical diagnosis of hyper-IgD syndrome, approximately 15% of patients were compound heterozygous for the I268T variant and another pathogenic variant (PMID: 19011501, 24084495, 24470648); Published functional studies demonstrate decreased mevalonate kinase activity as compared with wild type (PMID: 10369261); 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: 24088041, 11313768, 15536479, 29290516, 34525209, 34145613, 32060250, 23692791, 21425920, 10369262, 10417275, 11313769, 25897835, 24470648, 26116953, 26990548, 18839211, 10896296, 24084495, 31028937, 31474985, 31589614, 36242899, 35916082, 31964843, 37700301, 33815380, 35753512, 19011501, 10369261) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MVK: PM3:Very Strong, PM2, PS3:Supporting -

Feb 15, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PM2, PM3, PS3, PS4 -

Hyperimmunoglobulin D with periodic fever

Pathogenic:3Other:1

Mar 24, 2022

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Dec 12, 2023

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.803T>C (p.Ile268Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251464 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MVK causing Hyper-IgD syndrome (0.00015 vs 0.0056), allowing no conclusion about variant significance. c.803T>C has been reported in the literature in multiple individuals affected with Hyper-IgD syndrome (e.g. Houten_1999, Cuisset_2001, Simon_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (Houten_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10369261, 11313769, 16234278). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mevalonic aciduria

Pathogenic:2

Apr 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 15, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:2

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 268 of the MVK protein (p.Ile268Thr). This variant is present in population databases (rs104895304, gnomAD 0.03%). This missense change has been observed in individuals with mevalonate kinase deficiency and hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) (PMID: 10369261, 10401001, 10417275, 11313769, 19011501, 21425920, 23692791, 24470648, 26116953, 27142780, 27213830). ClinVar contains an entry for this variant (Variation ID: 11932). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MVK protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MVK function (PMID: 10369261, 10401001, 10417275). For these reasons, this variant has been classified as Pathogenic. -

not specified

Pathogenic:1

Nov 16, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Mar 25, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). _x000D_ _x000D_ 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. -

MVK-related disorder

Pathogenic:1

Jun 10, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.803T>C;p.(Ile268Thr) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clivar ID: 11932; PMID: 33917151; 24470648; 28359055; 24084495; 11313769) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28359055) - PS3_moderate. The variant is present at low allele frequencies population databases (rs104895304– gnomAD 0.001709%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Ile268Thr) was detected in trans with a Pathogenic variant (PMID: 33917151; 24470648; 11313769) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 24084495) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -

Hyperimmunoglobulin D with periodic fever;C1959626:Mevalonic aciduria

Pathogenic:1

Sep 17, 2014

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [V377I] in a 21-year-old female with FTT in infancy, childhood developmental delay, hypermobile joints, muscle soreness, fatigue, obesity, recurrent infections, anemia, anxiety and depression, overbite, flat feet, unexplained fevers, family history of EDS. Variant pathogenic in recessive state; heterozygotes are carriers. -

Autoinflammatory syndrome

Pathogenic:1

Jan 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Pathogenic:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;T;T;D

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

.;.;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;.;.;H

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.9

D;D;.;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0030

D;D;.;.

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.89

P;D;D;P

Vest4

0.81

MVP

0.99

MPC

1.2

ClinPred

0.78

GERP RS

4.6

Varity_R

0.63

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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