ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.2338C>A (p.Pro780Thr) (rs104895154)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217446 SCV000279570 uncertain significance not provided 2016-10-28 criteria provided, single submitter clinical testing The P780T variant has been published previously in association with both mild FMF as well as palindromic rheumatism (Goulielmos et al., 2006; Cañete et al., 2007). The variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. P780T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to 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.
Blueprint Genetics RCV000217446 SCV000927692 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing
Mendelics RCV000083763 SCV001139802 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000083763 SCV001217160 uncertain significance Familial Mediterranean fever 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 780 of the MEFV protein (p.Pro780Thr). The proline residue is weakly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs104895154, ExAC 0.008%). This variant has been observed in individuals affected with clinical features of MEFV-related conditions (PMID: 16730661, 17665427). ClinVar contains an entry for this variant (Variation ID: 97511). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The threonine 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.
Illumina Clinical Services Laboratory,Illumina RCV000083763 SCV001277618 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 RCV000083763 SCV000115859 not provided Familial Mediterranean fever no assertion provided not provided

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