rs104895317

Positions:

chr12-109595142-G-A

Variant summary

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

The NM_000431.4(MVK):c.1000G>A(p.Ala334Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,614,018 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 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

MVK
NM_000431.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 6.95

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:

MVK (HGNC:):

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, 0.863

PP5

Variant 12-109595142-G-A is Pathogenic according to our data. Variant chr12-109595142-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109595142-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MVK	NM_000431.4 linkuse as main transcript	c.1000G>A	p.Ala334Thr	missense_variant	10/11	ENST00000228510.8	NP_000422.1	Q03426B2RDU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8 linkuse as main transcript	c.1000G>A	p.Ala334Thr	missense_variant	10/11	1	NM_000431.4	ENSP00000228510.3		Q03426

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000956

AC:

AN:

251156

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000131

AC:

192

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000163

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000178

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the MVK protein (p.Ala334Thr). This variant is present in population databases (rs104895317, gnomAD 0.02%). This missense change has been observed in individual(s) with mevalonate kinase deficiency and retinitis pigmentosa (PMID: 9334262, 10401001, 12563048, 16435210, 19786432, 24084495, 28095071). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11930). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MVK function (PMID: 9334262). For these reasons, this variant has been classified as Pathogenic. -

Hyperimmunoglobulin D with periodic fever

Pathogenic:1Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2013	- -

Mevalonic aciduria

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2013

- -

Hyperimmunoglobulin D with periodic fever;C1959626:Mevalonic aciduria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PS3_Moderate+PM3_VeryStrong+PP4+PP1 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 30, 2022

The MVK c.1000G>A; p.Ala334Thr variant (rs104895317) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with mevalonate kinase deficiency (Balgobind 2005, Brennenstuhl 2021, Gattorno 2009, Hinson 1997, Prietsch 2003, Siemiatkowska 2013). This variant is found in the non-Finnish European population with an allele frequency of 0.02% (22/128940 alleles) in the Genome Aggregation Database. The alanine at codon 334 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.862). Consistent with these predictions, functional studies indicate the variant protein has reduced enzymatic activity in vitro and in patient cells (Hinson 1997). Based on available information, this variant is considered to be pathogenic. References: Balgobind B et al. Retinitis pigmentosa in mevalonate kinase deficiency. J Inherit Metab Dis. 2005;28(6):1143-5. PMID: 16435210. Brennenstuhl et al. Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria. J Inherit Metab Dis. 2021 Sep;44(5):1272-1287. PMID: 34145613 Gattorno M et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009 Oct;124(4):e721-8. PMID: 1978643 Hinson DD et al. Identification of an active site alanine in mevalonate kinase through characterization of a novel mutation in mevalonate kinase deficiency. J Biol Chem. 1997 Oct 17;272(42):26756-60. PMID: 9334262. Prietsch V et al. Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum. Pediatrics. 2003 Feb;111(2):258-61. PMID: 12563048. Siemiatkowska AM et al. Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa. Ophthalmology. 2013 Dec;120(12):2697-2705. PMID: 24084495. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

.;D;D;D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;.;.;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

.;H;.;.;H

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.9

D;D;D;.;.

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

D;D;D;.;.

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

.;D;D;D;D

Vest4

0.73

MVP

0.98

MPC

0.81

ClinPred

0.97

GERP RS

4.5

Varity_R

0.92

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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