ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.460T>C (p.Ser154Pro) (rs756975501)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218924 SCV000279033 uncertain significance not provided 2015-04-27 criteria provided, single submitter clinical testing The S154P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It 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 across species and in-silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues (E148Q/V, R151S, E163A, E167D) have been reported in the Human Gene Mutation Database in association with familial Mediterranean fever (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant..
Invitae RCV000695122 SCV000823602 uncertain significance Familial Mediterranean fever 2019-03-23 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 154 of the MEFV protein (p.Ser154Pro). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs756975501, ExAC 0.01%). This variant has been reported in individuals in the Infevers database (PMID: 12520003). ClinVar contains an entry for this variant (Variation ID: 234355). 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.
Integrated Genetics/Laboratory Corporation of America RCV001193204 SCV001361910 uncertain significance not specified 2019-03-08 criteria provided, single submitter clinical testing Variant summary: MEFV c.460T>C (p.Ser154Pro) 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 3.1e-05 in 257664 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.460T>C has been reported in the literature in individuals affected with Familial Mediterranean Fever (Berdeli 2013, Balta 2018, Lane 2013, Martorana 2013, Rowczenio 2013) and also in a patient with primary immunodeficiency (Gallo 2016). These reports do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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