rs28934897

Variant names:

• chr12-109596515-G-A
• rs28934897
• NM_000431.4:c.1129G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 14P and 2B. PS3 PM1 PP5_Very_Strong BP4 BS2_Supporting

The NM_000431.4(MVK):​c.1129G>A​(p.Val377Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0021 in 1,612,856 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000538050: Functional studies have shown reduced or undetectable mevalonate kinase activity and protein expression in affected individuals, indicating this variant likely affects protein stability and function (Houten et al., 1999)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (3 hom.)
• Consequence: MVK NM_000431.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:48 O:2
• Conservation: PhyloP100: 5.08
• Publications: 135 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
• mevalonate kinase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mevalonic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000538050: Functional studies have shown reduced or undetectable mevalonate kinase activity and protein expression in affected individuals, indicating this variant likely affects protein stability and function (Houten et al., 1999).; SCV000712172: It has been demonstrated to lead to reduced enzymatic activity in vitro (Houten 1999).; SCV003928976: The variant is associated with an MK activity of approximately 40% of WT in E.coli lysates and that it was undetectable by immunoblot in fibroblast lysates from HIDS patients, suggesting it also impacts protein stability (Houten_1999).; SCV006584319: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 10369261)."; SCV000279123: Published functional studies indicate that p.(V377I) leads to a decrease in enzyme activity and decreased stability when expressed in E. coli (Houten et al., 1999);; SCV001548926: "However, functional studies expressing cDNA constructs containing the V325I variant in E. coli have demonstrated decreased mevalonate kinase (MK) protein activity compared to wildtype (Houten_1999_PMID:10369261). Decreased MK activity was also found in lymphocytes and fibroblasts from patients with the V325I variant (Houten_1999_PMID:10369261)."; SCV000634151: Experimental studies have shown that this missense change affects MVK function (PMID: 10369261, 26977311).; SCV003740446: Functional studies showed that this alteration results in reduced enzyme activity (Houten, 1999; Messer, 2016).; SCV005397680: Studies examining the functional consequence of this variant have found reduced or undetectable mevalonate kinase activity and MK protein expression in affected individuals (PMID: 10369261).; SCV005399255: "This variant has strong functional evidence supporting abnormal protein function. Immunoblot analysis of patient lymphocytes showed minimal MK activity (PMID: 10369261)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000431.4
• PP5: Variant 12-109596515-G-A is Pathogenic according to our data. Variant chr12-109596515-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01983887). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000431.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	NM_000431.4	MANE Select	c.1129G>A	p.Val377Ile	missense	Exon 11 of 11	NP_000422.1	Q03426
	MVK	NM_001414512.1		c.1204G>A	p.Val402Ile	missense	Exon 12 of 12	NP_001401441.1
	MVK	NM_001114185.3		c.1129G>A	p.Val377Ile	missense	Exon 11 of 11	NP_001107657.1	B2RDU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	ENST00000228510.8	TSL:1 MANE Select	c.1129G>A	p.Val377Ile	missense	Exon 11 of 11	ENSP00000228510.3	Q03426
	MVK	ENST00000546277.6	TSL:5	c.1129G>A	p.Val377Ile	missense	Exon 11 of 11	ENSP00000438153.2	Q03426
	MVK	ENST00000878306.1		c.1129G>A	p.Val377Ile	missense	Exon 11 of 11	ENSP00000548365.1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00158 AC: 393 AN: 249414 AF XY: 0.00160

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00142

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00216 AC: 3159 AN: 1460542 Hom.: 3 Cov.: 31 AF XY: 0.00210 AC XY: 1523 AN XY: 726670

African (AFR) AF: 0.000657 AC: 22 AN: 33478

American (AMR) AF: 0.00132 AC: 59 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86256

European-Finnish (FIN) AF: 0.00124 AC: 65 AN: 52230

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5744

European-Non Finnish (NFE) AF: 0.00251 AC: 2786 AN: 1111912

Other (OTH) AF: 0.00214 AC: 129 AN: 60362

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74474

African (AFR) AF: 0.000409 AC: 17 AN: 41574

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00247 AC: 168 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00159 Hom.: 1

Bravo AF: 0.00134

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00140 AC: 170

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
18	-	-	Hyperimmunoglobulin D with periodic fever (18)
17	-	-	not provided (17)
3	-	-	MVK-related disorder (3)
2	-	-	Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria (4)
2	-	-	Mevalonic aciduria (2)
1	-	-	Autoinflammatory syndrome (1)
1	-	-	autosomal recessive MVK-related disorders (1)
1	-	-	Hyperimmunoglobulin D with periodic fever;C1959626:Mevalonic aciduria (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Porokeratosis 3, disseminated superficial actinic type (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.071	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.55
Sift	Benign	0.10	T
Sift4G	Uncertain	0.036	D
Polyphen		0.33	B
Vest4		0.21
MVP		0.77
MPC		0.30
ClinPred		0.026	T
GERP RS		3.2
Varity_R		0.095
gMVP		0.75
Mutation Taster		=11/89	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: rs28934897; hg19: chr12-110034320; COSMIC: COSV57332186;