ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1370C>T (p.Ala457Val) (rs104895151)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000512979 SCV000279049 uncertain significance not provided 2020-11-25 criteria provided, single submitter clinical testing Reported as heterozygous in an individual with fibromyalgia syndrome and an unrelated individual with FMF and small fiber neuropathy; both individuals were also heterozygous for the E148Q, P369S and R408Q variants, with all 4 variants on the same allele (in cis) (Feng et al., 2009; Shinkarevsky et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20041150, 27332769, 29579081, 32133669)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512979 SCV000608744 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
Invitae RCV000083692 SCV000629021 likely benign Familial Mediterranean fever 2020-11-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855597 SCV000696045 uncertain significance not specified 2019-06-14 criteria provided, single submitter clinical testing Variant summary: MEFV c.1370C>T (p.Ala457Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 252058 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00028 vs 0.022), allowing no conclusion about variant significance. c.1370C>T has been reported in the literature in individuals affected with Familial Mediterranean Fever (Lainka_2012, Mneimneh_2016). It was also reported in one heterozygous patient presented with Fibromyalgia Syndrome who had inherited the variant from his apparently unaffected heterozygous father (Fen_2009). 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 provisional status for c.1370C>T (Van Gijn_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional data of functional or clinical significance become available.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000512979 SCV000885684 uncertain significance not provided 2017-06-06 criteria provided, single submitter clinical testing The MEFV c.1370C>T; p.Ala457Val variant (rs104895151) has been reported in an individual with periodic fever syndrome (Infevers database), and another individual with fibromyalgia syndrome (Feng 2009). However, in the latter case, the variant was paternally inherited, and found in-cis with p.Glu148Gln, p.Pro369Ser and p.Arg408Gln, with no variants detected on the maternal chromosome (Feng 2009). The variant is listed in ClinVar (Variation ID: 97441), and observed in the general population at an overall frequency of 0.03% (73/277128 alleles) in the Genome Aggregation Database. The alanine at residue 457 is weakly conserved and computational algorithms (PolyPhen-2, SIFT) predict that the variant has no impact on the protein. Due to the limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Infevers database: http://fmf.igh.cnrs.fr/ISSAID/infevers/search.php?n=1 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.
Mendelics RCV000083692 SCV001139859 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000083692 SCV001276008 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001280972 SCV001468353 uncertain significance Familial Mediterranean fever; Familial mediterranean fever, autosomal dominant 2020-03-20 criteria provided, single submitter clinical testing MEFV NM_000243.2 exon 5 p.Ala457Val (c.1370C>T): This variant has been reported in the literature in at least 2 individuals with features of Familial Mediterranean Fever (FMF). This variant is often reported in cis with several other variants (p.Glu148Gln, p.Pro369Ser, p.Arg408Gln) as part of a complex heterozygote; however at least 1 individual was reported to have this variant in trans (Lainka 2012 PMID:22903357, Mneimneh 2016 PMID:n/a). Of note, this variant was also found in cis with the same variants in 1 patient with fibromyalgia (Feng 2009 PMID:20041150). This variant is present in 0.5% (54/10368) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3297233-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:97441) and the infevers database (https://infevers.umai-montpellier.fr/web/detail_mutation.php). This variant amino acid Valine (Val) is present in 9 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083692 SCV000115780 not provided Familial Mediterranean fever no assertion provided not provided

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