rs104895369

chr12-109579850-AGGAGGTT-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000431.4(MVK):c.277_283del(p.Glu93GlnfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MVK NM_000431.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 3.14

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-109579850-AGGAGGTT-A is Pathogenic according to our data. Variant chr12-109579850-AGGAGGTT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97579.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, not_provided=1, Uncertain_significance=1}. Variant chr12-109579850-AGGAGGTT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVK	NM_000431.4	c.277_283del	p.Glu93GlnfsTer38	frameshift_variant	4/11	ENST00000228510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000228510.8	c.277_283del	p.Glu93GlnfsTer38	frameshift_variant	4/11	1	NM_000431.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461886 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2023

This sequence change creates a premature translational stop signal (p.Glu93Glnfs*38) in the MVK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MVK are known to be pathogenic (PMID: 16835861, 17105862, 23834120). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mevalonate kinase deficiency (PMID: 16835861). ClinVar contains an entry for this variant (Variation ID: 97579). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 30, 2022

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MVK-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 05, 2017

The MVK c.277_283delGAGGTTG (p.Glu93GlnfsTer38) variant results in a frameshift and is predicted to result in premature termination of the protein. The variant has been reported in a single study in which it is found in a single patient with mevalonate kinase deficiency in a compound heterozygous state (Mandey et al. 2006). Control data are unavailable for the p.Glu93GlnfsTer38 variant which not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database. Based on the limited evidence and the potential impact of frameshift variants, the p.Glu93GlnfsTer38 variant is classified as a variant of unknown significance but suspicious for pathogenicity for MVK-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Hyperimmunoglobulin D with periodic fever Other:1

not provided, no classification provided

literature only

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs104895369; hg19: chr12-110017655;