rs104895324

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000431.4(MVK):c.1139A>G(p.His380Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,612,310 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H380H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

MVK
NM_000431.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1O:1

Conservation

PhyloP100: 7.23

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000431.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

PP5

Variant 12-109596525-A-G is Pathogenic according to our data. Variant chr12-109596525-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97569.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=1, not_provided=1}. Variant chr12-109596525-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVK	NM_000431.4 linkuse as main transcript	c.1139A>G	p.His380Arg	missense_variant	11/11	ENST00000228510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000228510.8 linkuse as main transcript	c.1139A>G	p.His380Arg	missense_variant	11/11	1	NM_000431.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249470

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000796

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1460264

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726544

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.0000477

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000306

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 08, 2018	The MVK c.1139A>G; p.His380Arg variant (rs104895324) is reported in the medical literature in individuals with mevalonate kinase deficiency, hyperimmunoglobulinemia D and periodic fever syndrome (Shendi 2014, Tahara 2011, Wickiser 2005). The variant is reported in the ClinVar database (Variation ID: 97569). This variant is found in the non-Finnish European population with an overall allele frequency of 0.007% (10/126246 alleles) in the Genome Aggregation Database. The histidine at codon 380 is moderately conserved across species but computational algorithms (PolyPhen-2, SIFT) predict conflicting effects of this variant on protein structure/function. Considering available information, the clinical significance of this variant cannot be determined with certainty. Pathogenic MVK variants are causative for autosomal recessive hyper IgD syndrome (MIM: 260920) and mevalonic aciduria (MIM: 610377). References: Shendi HM et al. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol. 2014 Mar;20(2):103-5. Tahara M et al. Patient with neonatal-onset chronic hepatitis presenting with mevalonate kinase deficiency with a novel MVK gene mutation. Mod Rheumatol. 2011 Dec;21(6):641-5. Wickiser JE and Saulsbury FT. Henoch-Schonlein purpura in a child with hyperimmunoglobulinemia D and periodic fever syndrome. Pediatr Dermatol. 2005 Mar-Apr;22(2):138-41. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 27, 2022	PP3, PM1, PM2_supporting, PS4_moderate -

Hyperimmunoglobulin D with periodic fever

Pathogenic:1Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 05, 2021	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

MVK-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2023

The MVK c.1139A>G variant is predicted to result in the amino acid substitution p.His380Arg. This variant has been reported, along other variants in MVK in the compound heterozygous state and phase unknown, in individuals with hyper-IgD and periodic fever syndrome (HIDS) (Wickiser and Saulsbury. 2005. PubMed ID: 15804303; Tahara et al. 2011. PubMed ID: 21399979; Shendi et al. 2014. PubMed ID: 24561416; Papa et al. 2017. PubMed ID: 29047407). A long-term study of 103 individuals with hyperimmunoglobulinemia D syndrome found that the c.1139A>G (p.His380Arg) was present at an allele frequency of 1.5% and was a prevalent variant seen in patients (van der Hilst et al. 2008. PubMed ID: 19011501). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-110034330-A-G) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from pathogenic to likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/97569/). This variant is interpreted as likely pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2023

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 380 of the MVK protein (p.His380Arg). This variant is present in population databases (rs104895324, gnomAD 0.008%). This missense change has been observed in individual(s) with hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) (PMID: 15804303, 19011501, 21399979, 24561416, 29047407). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 97569). 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 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.43

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

T;.;.;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.1

D;D;D;.;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0040

D;D;D;.;.

Sift4G

Uncertain

0.021

D;T;T;T;T

Polyphen

1.0, 1.0

.;D;D;D;D

Vest4

0.93

MVP

0.96

MPC

1.3

ClinPred

0.75

GERP RS

5.1

Varity_R

0.61

gMVP

0.90

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