12-109591262-C-T

Variant summary

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

The NM_000431.4(MVK):​c.790C>T​(p.Leu264Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,246 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L264V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

MVK
NM_000431.4 missense

Scores

4
10
5

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 0.221
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000431.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.912
PP5
Variant 12-109591262-C-T is Pathogenic according to our data. Variant chr12-109591262-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 97625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109591262-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MVKNM_000431.4 linkc.790C>T p.Leu264Phe 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
MVKENST00000228510.8 linkc.790C>T p.Leu264Phe missense_variant Exon 9 of 11 1 NM_000431.4 ENSP00000228510.3 Q03426

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152246
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152246
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mevalonic aciduria Pathogenic:1
Jul 23, 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.790C>T (p.Leu264Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes (gnomAD). c.790C>T has been reported in the literature in multiple individuals affected with Mevalonic aciduria (e.g. Hinson_1999, Houten_2001). 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 a severe loss of protein expression and enzymatic activity (Hinson_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10417275, 11313768). ClinVar contains an entry for this variant (Variation ID: 97625). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria Pathogenic:1
Jan 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 264 of the MVK protein (p.Leu264Phe). This variant is present in population databases (rs104895315, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of mevalonate kinase deficiency and mevalonate kinase deficiency (PMID: 10417275, 11313768, 19786432, 22038276, 22566169, 29047407). ClinVar contains an entry for this variant (Variation ID: 97625). 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 not expected to disrupt MVK protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MVK function (PMID: 10417275). For these reasons, this variant has been classified as Pathogenic. -

Hyperimmunoglobulin D with periodic fever Other:1
-
Unité médicale des maladies autoinflammatoires, CHRU Montpellier
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Benign
16
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;T;T;D
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.29
N
LIST_S2
Uncertain
0.86
.;.;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.91
D;D;D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.5
M;.;.;M
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-2.5
N;N;.;.
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0050
D;D;.;.
Sift4G
Uncertain
0.011
D;D;D;D
Polyphen
0.98
D;P;P;D
Vest4
0.79
MutPred
0.86
Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);
MVP
0.98
MPC
0.57
ClinPred
0.91
D
GERP RS
1.5
Varity_R
0.28
gMVP
0.87

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.

Other links and lift over

dbSNP: rs104895315; hg19: chr12-110029067; API