rs397514570

Variant names:

• chr12-109590857-T-C
• rs397514570
• NM_000431.4:c.764T>C
• MVK p.Leu255Pro

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000431.4(MVK):​c.764T>C​(p.Leu255Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MVK NM_000431.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.49
• Publications: 3 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: Labcorp Genetics (formerly Invitae), G2P
• hyperimmunoglobulinemia D with periodic fever

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000431.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-109590857-T-C is Pathogenic according to our data. Variant chr12-109590857-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 39724.Status of the report is no_assertion_criteria_provided, 0 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.764T>C	p.Leu255Pro	missense	Exon 8 of 11	NP_000422.1	Q03426
	MVK	NM_001414512.1		c.839T>C	p.Leu280Pro	missense	Exon 9 of 12	NP_001401441.1
	MVK	NM_001114185.3		c.764T>C	p.Leu255Pro	missense	Exon 8 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.764T>C	p.Leu255Pro	missense	Exon 8 of 11	ENSP00000228510.3	Q03426
	MVK	ENST00000546277.6	TSL:5	c.764T>C	p.Leu255Pro	missense	Exon 8 of 11	ENSP00000438153.2	Q03426
	MVK	ENST00000878306.1		c.764T>C	p.Leu255Pro	missense	Exon 8 of 11	ENSP00000548365.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.000131 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Porokeratosis 3, disseminated superficial actinic type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.035
Eigen_PC	Benign	0.0063
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.5
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.74
Sift	Benign	0.30	T
Sift4G	Benign	0.34	T
Varity_R		0.66
gMVP		0.91
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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: rs397514570;

hg19: chr12-110028662;