rs121917790

chr12-109581517-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• 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 id is 11933.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-109581517-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVK	NM_000431.4	c.494C>T	p.Pro165Leu	missense_variant	5/11	ENST00000228510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000228510.8	c.494C>T	p.Pro165Leu	missense_variant	5/11	1	NM_000431.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000454 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 19, 2019

For these reasons, this allele has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individuals with clinical features consistent with hyper IgD syndrome or mevalonate kinase deficiency (PMID: 10369262, 29047407). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 11933). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 165 of the MVK protein (p.Pro165Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. -

Hyperimmunoglobulin D with periodic fever Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.84	T;T;.;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationTaster	Benign	0.96	A;A;A;A;A
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.9	D;D;N;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.011	D;D;T;.
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.26	.;.;B;B
Vest4		0.72, 0.76
MutPred		0.85		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121917790; hg19: chr12-110019322;