rs104895324

Variant names:

• chr12-109596525-A-G
• rs104895324
• NM_000431.4:c.1139A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_Very_Strong

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 Likely pathogenic (★★). 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.23
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• porokeratosis 3, disseminated superficial actinic type

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hyperimmunoglobulinemia D with periodic fever

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• mevalonic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• porokeratosis of Mibelli

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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, 8 uncertain in NM_000431.4
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 97569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVK	NM_000431.4	c.1139A>G	p.His380Arg	missense_variant	Exon 11 of 11	ENST00000228510.8	NP_000422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8	c.1139A>G	p.His380Arg	missense_variant	Exon 11 of 11	1	NM_000431.4	ENSP00000228510.3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152046 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000361 AC: 9 AN: 249470 AF XY: 0.0000518

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1460264 Hom.: 0 Cov.: 31 AF XY: 0.0000317 AC XY: 23 AN XY: 726544

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111914

Other (OTH) AF: 0.0000497 AC: 3 AN: 60360

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74272

African (AFR) AF: 0.0000242 AC: 1 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000306 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria Pathogenic:2

Jun 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MVK protein function. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Aug 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MVK c.1139A>G; p.His380Arg variant (rs104895324, ClinVar Variation ID: 97569) is reported in the medical literature in individuals with mevalonate kinase deficiency, hyperimmunoglobulinemia D and periodic fever syndrome (Shendi 2014, Tahara 2011, Wickiser 2005). 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. Computational analyses predict that this variant is deleterious (REVEL: 0.796). Based on available information, this variant is considered to be likely pathogenic. References: Papa R et al. A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. Orphanet J Rare Dis. 2017 Oct 18;12(1):167. PMID: 29047407. Shendi HM et al. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol. 2014 Mar;20(2):103-5. PMID: 24561416 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. PMID: 21399979 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. PMID: 15804303 van der Hilst JCH et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore). 2008 Nov;87(6):301-310. PMID: 19011501. -

Apr 27, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM1, PM2_supporting, PS4_moderate -

Hyperimmunoglobulin D with periodic fever Pathogenic:1 Other:1

Aug 05, 2021

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mevalonic aciduria Pathogenic:1

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mevalonic aciduria (MIM#610377). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial variability has been reported (PMID: 32822427). In addition, this gene may be associated with a spectrum of disease, including severe perinatal presentations with hydrops (PMID: 27012807). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 10 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with mevalonate kinase deficiency and hyperimmunoglobulinemia D and Periodic Fever Syndrome (ClinVar, PMIDs: 15804303; 29047407; 24561416; 21399979). (SP) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000431.2:c.709A>T; p.(Thr237Ser)) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

MVK-related disorder Pathogenic:1

Apr 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	.;T;T;T;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;.;.;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.6	.;M;.;.;M
PhyloP100		7.2
PrimateAI	Uncertain	0.56	T
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	D
GERP RS		5.1
Varity_R		0.61
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104895324; hg19: chr12-110034330;