ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.986G>A (p.Arg329His) (rs104895112)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000585083 SCV000279045 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing The R329H variant in the MEFV gene has been reported previously in the heterozygous state in multiple unrelated individuals with familial Mediterranean fever (Feng et al., 2009; Lainka et al., 2012; Yao et al., 2015). This variant is observed in 111/10,054 alleles (1.1%) from individuals of Ashkenazi Jewish background, and 428/274,062 global alleles (0.16%), in large population cohorts including 2 homozygous control individuals (Lek et al., 2016). The R329H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret R329H as a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000585083 SCV000338237 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000855598 SCV000604184 uncertain significance not specified 2018-07-31 criteria provided, single submitter clinical testing The MEFV c.986G>A; p.Arg329His variant (rs104895112) has been described in the literature in one individual with fibromyalgia (Feng 2009), but has not been described in individuals with Familial Mediterranean Fever. This variant is listed in ClinVar (Variation ID: 97557) and observed in the Genome Aggregation Database with an allele frequency of 0.16 % (428/274062 alleles, 2 homozygotes). The arginine at position 329 is weakly conserved (Alamut v2.10) and a histidine is found in at least two mammals. Additionally, computational programs (SIFT, PolyPhen-2) predict this variant has minimal impact on MEFV protein structure or function. Due to the limited information regarding the p.Arg329His variant, its clinical significance could not be determined with certainty. References: Feng J et al. Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels. PLoS One. 2009. 4(12):e8480.
Invitae RCV000083809 SCV000629050 likely benign Familial Mediterranean fever 2019-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585083 SCV000692832 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855598 SCV000696084 likely benign not specified 2020-02-16 criteria provided, single submitter clinical testing Variant summary: MEFV c.986G>A (p.Arg329His) 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. A recent report utilizing the meta predictor tool, REVEL (Rare Exome Variant Ensemble Learner) to assess the pathogenicity of MEFV variants with ambiguous classification proposed a likely benign outcome for this variant (Accetturo_2019). In this study, REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Autoinflammatory Diseases. The variant allele was found at a frequency of 0.0016 in 249988 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever allowing no conclusion about variant significance. c.986G>A, has been reported in the literature in patients in association with FMF, atypical FMF, MS and fibromyalgia (example, Feng_2009, Kuempfel_2012, Berdeli_2012, Pauwels_2013, Heshin-Bekenstein_2015, Yao_2016, Balta_2018, Zhang_2018). The phenotypic variability seen with this variant and genotypic information are not clearly specific to FMF, and at least some of these reported FMF patients were not responsive to colchicine therapy (Hashkes_2012). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. Recently, the International Study Group for Systemic Autoinflammatory Diseases (INSIAD) involving experts on hereditary recurrent fever genetics, provided a classification of likely benign with a validated status for c.986G>A (Van Gijn_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. At-least one submitter has re-classified this variant as likely benign since our previous evaluation. Another submitter has cited overlapping evidence utilized in the context of our evaluation. We have followed this variant for over three years and previously classified it as a VUS. In our review of published evidence spanning over 10 years (2009-2019), the majority of evidence appears to point toward a non-pathogenic outcome however more data is required to conclusively determine the clinical consequences of this variant. Therefore, based on the evidence outlined above, this variant in isolation is re-classified as likely benign.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000083809 SCV000782513 uncertain significance Familial Mediterranean fever 2016-10-28 criteria provided, single submitter clinical testing
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735285 SCV000854438 uncertain significance Cryptorchidism; Global developmental delay; Seizures; Abnormality of the anterior fontanelle; Macrocephalus; Deep plantar creases; Abnormality of the cerebral white matter; Central hypotonia criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000083809 SCV001279959 uncertain significance Familial Mediterranean fever 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083809 SCV000115910 not provided Familial Mediterranean fever no assertion provided not provided
GenomeConnect, ClinGen RCV000083809 SCV001423314 not provided Familial Mediterranean fever no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 06-02-2016 by Lab or GTR ID 506013. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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