rs28934897

Variant names:

• chr12-109596515-G-A
• rs28934897
• NM_000431.4:c.1129G>A
• MVK p.Val377Ile

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PS3PP5_Strong

The NM_000431.4(MVK):c.1129G>A (p.Val377Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0021 (AC=3,382) in the gnomAD database across 1,612,856 control chromosomes, including 4 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00243. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/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. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• 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:52 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, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• disseminated superficial actinic porokeratosis

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); 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)."
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (52/52 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000431.4. You can select a different transcript below to see updated classification 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	B2RDU6
	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	Q03426

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	Q03426

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00147	AC:223	Hom:1	AN:152196	Cov:33
GnomAD2 exomes	AF: 0.00158	AC:393	Hom:	AN:249414	Cov:
GnomAD4 exome	AF: 0.00216	AC:3159	Hom:3	AN:1460542	Cov:31
GnomAD4 genome	AF: 0.00146	AC:223	Hom:1	AN:152314	Cov:33
TOPMed (Bravo)	AF: 0.00134	AC:354	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00162	AC:765	Hom:1	AN:471894	Cov:
Local & regional cohorts 7 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00256	AC:6	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00169	AC:22	Hom:	AN:13006	Cov:
Qatari Genome	AF: 0.00320	AC:6	Hom:	AN:1868	Cov:
Turkish Variome	AF: 0.00360	AC:24	Hom:0	AN:6662	Cov:
UK10K	AF: 0.00357	AC:27	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 13 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00144 *	16	11112	0.00131 *	23	17618
BipEx(Bipolar disorder (including schizoaffective))	0.00236	67	28420	0.00194	56	28844
Epi25(Epilepsy)	0.00176	74	41958	0.00199	133	66888
SCHEMA(Schizophrenia)	0.00116	136	117240	0.00113	206	181816

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
19	-	-	Hyperimmunoglobulin D with periodic fever (19)
17	-	-	not provided (17)
4	-	-	MVK-related disorder (4)
3	-	-	Mevalonic aciduria (3)
2	-	-	Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria (4)
2	-	-	Hyperimmunoglobulin D with periodic fever;C1959626:Mevalonic aciduria (2)
1	-	-	Autoinflammatory syndrome (1)
1	-	-	autosomal recessive MVK-related disorders (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Porokeratosis 3, disseminated superficial actinic type (1)
1	-	-	Retinal dystrophy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	7.2
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
FuncVEP CTI	Benign	0.023
GPN-Star LLR	N/A	-2.4
GPN-Star score	N/A	2.4
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.071	D
Mutation Taster	N/A	11/89	disease causing (ClinVar)
MutationAssessor	Uncertain	2.0	M
PhyloP100	Uncertain	5.1
popEVE	Benign	-3.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.55
Sift	Benign	0.10	T
Sift4G	Uncertain	0.036	D
Varity_R	N/A	0.095
VESM-3B	Benign	-6.2

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs28934897;

hg19: chr12-110034320;

COSMIC: COSV57332186;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar