Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001001442 | SCV001158680 | likely pathogenic | not specified | 2019-05-16 | criteria provided, single submitter | clinical testing | The MEFV c.2085G>C; p.Lys695Asn variant (rs104895208) is reported in the medical literature in individuals with familial Mediterranean fever (Berdeli 2011, Oztuzcu 2014). This variant is considered likely pathogenic by an expert group (Van Gijn 2018). Another variant in this codon, p.Lys695Arg, is considered pathogenic but may exhibit reduced penetrance (Bernot 1998). The c.2085G>C; p.Lys695Asn variant is listed in the ClinVar database (Variation ID: 97490) and in 2 out of 251486 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The amino acid at this position is moderately conserved and is located in the SPRY domain, but computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Most pathogenic MEFV variants occur in the SPRY domain (Manukyan 2016). Considering available information, this variant is classified as likely pathogenic. References: Berdeli A et al. Comprehensive analysis of a large-scale screen for MEFV gene mutations: do they truly provide a heterozygote advantage" in Turkey? Genet Test Mol Biomarkers. 2011 Jul-Aug;15(7-8):475-82. Bernot et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 7(8):1317-25. Manukyan G and Aminov R Update on Pyrin Functions and Mechanisms of Familial Mediterranean Fever. Front. Microbiol. 2016 7:456. Oztuzcu S et al. Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep. 2014;41(4):2601-7. Van Gijn ME et al. New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID). J Med Genet. 2018 Aug;55(8):530-537. " |
| Labcorp Genetics |
RCV000083742 | SCV003443427 | uncertain significance | Familial Mediterranean fever | 2022-04-30 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 695 of the MEFV protein (p.Lys695Asn). This variant is present in population databases (rs104895208, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of familial Mediterranean fever (PMID: 21413889, 24469716). ClinVar contains an entry for this variant (Variation ID: 97490). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. |
| Unité médicale des maladies autoinflammatoires, |
RCV000083742 | SCV000115836 | not provided | Familial Mediterranean fever | no assertion provided | not provided |