rs104895360
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000431.4(MVK):c.1162C>T(p.Arg388*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,611,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000431.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249020Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134922
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1459298Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 726114
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74368
ClinVar
Submissions by phenotype
Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria Pathogenic:2
This sequence change creates a premature translational stop signal (p.Arg388*) in the MVK gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the MVK protein. This variant is present in population databases (rs104895360, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with mevalonate kinase deficiency (PMID: 23146290, 23998246, 27012807). ClinVar contains an entry for this variant (Variation ID: 97572). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:2
MVK: PM3:Very Strong, PM2, PVS1:Moderate, PP4 -
The R388X nonsense mutation in the MVK gene has been reported previously in association with MKD disorders (Houten et al., 2000; Prasad et al., 2012). It was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R388X is predicted to cause loss of normal protein function through production of a truncated protein that is missing the last 9 amino acids of the normal MVK protein. -
Hyperimmunoglobulin D with periodic fever Pathogenic:1Other:1
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MVK-related disorder Pathogenic:1
The MVK c.1162C>T variant is predicted to result in premature protein termination (p.Arg388*). This variant has been reported to be causative for mevalonate kinase deficiency and Hyper IgD syndrome (Houten et al. 2000. PubMed ID: 11111075; Peciuliene et al. 2016. PubMed ID: 27012807; Prasad et al. 2012. PubMed ID: 23146290). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-110034353-C-T). Nonsense variants in MVK are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at