ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.322A>C (p.Ser108Arg) (rs104895103)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586697 SCV000279023 uncertain significance not provided 2016-07-27 criteria provided, single submitter clinical testing The S108R variant in the MEFV gene has been observed in patients with MEFV-related periodic fever syndromes who were either heterozygous for the variant or compound heterozygous with the V726A pathogenic variant (Medlej-Hashim et al., 2005; Salehzadeh et al., 2014; Kilinc et al., 2016). It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S108R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV001000180 SCV000696067 uncertain significance not specified 2019-10-04 criteria provided, single submitter clinical testing Variant summary: MEFV c.322A>C (p.Ser108Arg) 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 8.1e-06 in 247374 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.322A>C has been reported in the literature in individuals affected with Periodic Fever Syndrome (e.g. Gattorno_2009, Federici_2012) and familial Mediterranean fever (e.g. Medlej-Hashim_2005, Omenetti_2014, Ozen_2014, Papa_2017), without strong evidence for causality. These data do not allow any conclusion about variant significance. The variant was often reported along with the pathogenic V726A variant in individuals (LCA internal data and publications); publications from the same group of authors reported these two variants in compound heterozygosity without specifying though if parental testing was carried out to confirm this status (Gattorno_2009, Federici_2012), while a more recent study from the same group reported these two variants in cis in two FMF patients (Omenetti_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Furthermore, the experts international study group for systemic autoinflammatory diseases (INSAID) decided a consensus classification of uncertain significance for the variant (Van Gijn_2018). Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000083767 SCV000817485 uncertain significance Familial Mediterranean fever 2019-07-25 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 108 of the MEFV protein (p.Ser108Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with familial Mediterranean fever (FMF) (PMID: 16378925, 19786432, 29047407). ClinVar contains an entry for this variant (Variation ID: 97515). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Fulgent Genetics,Fulgent Genetics RCV000765292 SCV000896547 uncertain significance Familial Mediterranean fever; Familial mediterranean fever, autosomal dominant 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000083767 SCV001139895 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000180 SCV001156672 uncertain significance not specified 2019-04-06 criteria provided, single submitter clinical testing The MEFV c.322A>C; p.Ser108Arg variant (rs104895103) is reported in the literature in multiple individuals with MEFV-related periodic fever syndromes and has been reported as compound heterozygous with the pathogenic V726A allele (Federici 2012, Gattorno 2009, Kilinc 2016, Medlej-Hashim 2005). This variant is classified as uncertain in ClinVar (Variation ID: 97515). It is only observed in two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 108 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on currently available information, it is uncertain whether this variant is benign or disease-associated. REFERENCES Federici S et al. Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population. Ann Rheum Dis. 2012 Dec;71(12):1961-5. Gattorno M et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009 Oct;124(4):e721-8. Kilinc M et al. The report of sequence analysis on familial Mediterranean fever gene (MEFV) in South-eastern Mediterranean region (Kahramanmaras) of Turkey. Rheumatol Int. 2016 Jan;36(1):25-31. Medlej-Hashim M et al. Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet. 2005 Oct-Dec;48(4):412-20.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586697 SCV001247642 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083767 SCV000115863 not provided Familial Mediterranean fever no assertion provided not provided

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