chr12-109596453-C-A

Variant names:

• chr12-109596453-C-A
• rs104895342
• NM_000431.4:c.1067C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000431.4(MVK):​c.1067C>A​(p.Thr356Lys) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T356M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MVK NM_000431.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73
• Publications: 0 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
• mevalonic aciduria

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26451933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVK	NM_000431.4	c.1067C>A	p.Thr356Lys	missense_variant	Exon 11 of 11	ENST00000228510.8	NP_000422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8	c.1067C>A	p.Thr356Lys	missense_variant	Exon 11 of 11	1	NM_000431.4	ENSP00000228510.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

May 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MVK protein function. This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 356 of the MVK protein (p.Thr356Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with recurrent fevers (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1383170). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.24	.;T;T;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.85	D;.;.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Benign	1.6	.;L;.;.;L
PhyloP100		1.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N;N;N;.;.
REVEL	Uncertain	0.53
Sift	Benign	0.058	T;D;D;.;.
Sift4G	Uncertain	0.039	D;D;D;D;D
Polyphen		0.91, 0.047	.;P;B;B;P
Vest4		0.55
MutPred		0.58		.;Gain of ubiquitination at T356 (P = 0.0219);.;.;Gain of ubiquitination at T356 (P = 0.0219);
MVP		0.93
MPC		0.75
ClinPred		0.31	T
GERP RS		2.1
Varity_R		0.66
gMVP		0.87
Mutation Taster		=35/65	disease causing

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: rs104895342; hg19: chr12-110034258;