rs121917790

Variant names:

• chr12-109581517-C-T
• rs121917790
• NM_000431.4:c.494C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000431.4(MVK):​c.494C>T​(p.Pro165Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MVK NM_000431.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.19
• 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
• 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: Likely_pathogenic. The variant received 8 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 12-109581517-C-T is Pathogenic according to our data. Variant chr12-109581517-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 11933.Status of the report is criteria_provided_single_submitter, 1 stars.

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.494C>T	p.Pro165Leu	missense	Exon 5 of 11	NP_000422.1	Q03426
	MVK	NM_001414512.1		c.494C>T	p.Pro165Leu	missense	Exon 5 of 12	NP_001401441.1
	MVK	NM_001114185.3		c.494C>T	p.Pro165Leu	missense	Exon 5 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.494C>T	p.Pro165Leu	missense	Exon 5 of 11	ENSP00000228510.3	Q03426
	MVK	ENST00000546277.6	TSL:5	c.494C>T	p.Pro165Leu	missense	Exon 5 of 11	ENSP00000438153.2	Q03426
	MVK	ENST00000878306.1		c.494C>T	p.Pro165Leu	missense	Exon 5 of 11	ENSP00000548365.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000545 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hyperimmunoglobulin D with periodic fever (1)
1	-	-	Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.6	L
PhyloP100		2.2
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.011	D
Sift4G	Benign	0.11	T
Polyphen		0.26	B
Vest4		0.72
MutPred		0.85		Loss of helix (P = 0.0626)
MVP		0.88
MPC		0.42
ClinPred		0.41	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.55
Mutation Taster		=24/76	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: rs121917790; hg19: chr12-110019322;