ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512979 SCV000608744 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing
GeneDx RCV000512979 SCV000279049 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing The A457V variant has been reported in an individual with a reported periodic fever syndrome and has also been reported in an individual with fibromyalgia (Feng et al., 2009). In both instances, the affected individuals were also found to harbor E148Q, P369S and R408Q. However, in at least the Feng study, all four missense changes were observed on a single allele, with no mutations or variants reported on the opposite allele. In addition, one of the parents of the proband in the Feng study was found to harbor all four missense changes, though it was not clear if that parent had any abnormal clinical presentation. Therefore, it is not clear if the A457V variant is a rare missense change associated with an abnormal inflammatory response or if it is a benign polymorphism.
Integrated Genetics/Laboratory Corporation of America RCV000512979 SCV000696045 uncertain significance not provided 2017-06-26 criteria provided, single submitter clinical testing Variant summary: The MEFV c.1370C>T (p.Ala457Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not available) although these predictions have yet to be functionally assessed. This variant was found in 30/121534 control chromosomes at a frequency of 0.0002468, which does not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). Multiple publications cite the variant in affected individuals, predominantly co-occurring as a complex variant, E148Q (VUS in our internal database)/P369S/R408Q (both classified as VUS-possibly benign by our lab) (Lainka_Eur J Pediatr_2012, Mneimneh_OJRAD_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000083692 SCV000629021 uncertain significance Familial Mediterranean fever 2017-07-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 457 of the MEFV protein (p.Ala457Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs104895151, ExAC 0.03%). This variant has been reported in an individual affected with fibromyalgia who also carried p.Glu148Gln, p.Pro369Ser, and p.Arg408Gln on the same chromosome (in cis) (PMID: 20041150). The haplotype was also found in this individual's father, though it is unclear if the father was affected with any disease. This variant has also been reported in an individual (who also carried the p.Glu148Gln, p.Pro369Ser, and p.Arg408Gln variants) in the Infevers database (PMID: 18409191). ClinVar contains an entry for this variant (Variation ID: 97441). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083692 SCV000115780 not provided Familial Mediterranean fever no assertion provided not provided

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