ClinVar Miner

Submissions for variant NM_000431.4(MVK):c.863C>T (p.Pro288Leu)

gnomAD frequency: 0.00004  dbSNP: rs104895355
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000688958 SCV000816590 uncertain significance Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2022-07-25 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 288 of the MVK protein (p.Pro288Leu). This variant is present in population databases (rs104895355, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MVK-related conditions. ClinVar contains an entry for this variant (Variation ID: 97634). 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. 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.
GeneDx RCV001664395 SCV001873556 uncertain significance not provided 2023-11-22 criteria provided, single submitter clinical testing Reported in association with Hyper-IgD syndrome, however, no patient information is available (PMID: 29062244); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 30936962, 29062244)
Fulgent Genetics, Fulgent Genetics RCV000688958 SCV002776104 uncertain significance Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2024-06-05 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV003448262 SCV004176371 uncertain significance Mevalonic aciduria 2023-02-14 criteria provided, single submitter clinical testing The missense c.863C>T (p.Pro288Leu) variant in MVK gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Pro288Leu variant is reported with an allele frequency of 0.006% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance (multiple submissions). The amino acid change p.Pro288Leu in MVK is predicted as conserved by GERP++. The amino acid Pro at position 288 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004800278 SCV005423378 uncertain significance not specified 2024-10-04 criteria provided, single submitter clinical testing Variant summary: MVK c.863C>T (p.Pro288Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251386 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MVK causing Hyper-IgD syndrome (5.6e-05 vs 0.0056), allowing no conclusion about variant significance. c.863C>T has been reported in the literature in individuals affected with Hyper-IgD syndrome without strong evdidence of causality (e.g. Li_2024). This report does not provide unequivocal conclusions about association of the variant with Hyper-IgD syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 38983106). ClinVar contains an entry for this variant (Variation ID: 97634). Based on the evidence outlined above, the variant was classified as uncertain significance.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083886 SCV000115992 not provided Hyperimmunoglobulin D with periodic fever no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.