Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001383593 | SCV001582786 | pathogenic | Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever | 2024-10-29 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 215 of the MVK protein (p.Arg215Gln). This variant is present in population databases (rs104895303, gnomAD 0.003%). This missense change has been observed in individual(s) with mevalonate kinase deficiency (PMID: 11313769, 15536479, 26409462, 27213830). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 97608). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MVK protein function. For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV004786362 | SCV005399254 | likely pathogenic | Mevalonic aciduria | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive hyper-IgD syndrome (MIM#260920) and mevalonic aciduria (MIM#610377). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (7 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. Variant p.(Arg215Gly) has a higher Grantham score (GS = 125) and has been reported once in a patient with autosomal dominant porokeratosis (PMID: 24551296). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is associated with hyper-IgD syndrome (Infevers database). There are at least 7 unrelated patients affected with mevalonate kinase deficiency who were identified as compound heterozygous for this variant plus another variant in the MVK gene. Multiple of these patients were in trans with the p.Val377Ile variant (PMIDs: 29047407, 26409462, 15536479, 11313769). (SP) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Unité médicale des maladies autoinflammatoires, |
RCV000083860 | SCV000115965 | not provided | Hyperimmunoglobulin D with periodic fever | no assertion provided | not provided |