ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1532C>T (p.Ala511Val) (rs144270019)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000801307 SCV000941078 uncertain significance Familial Mediterranean fever 2019-08-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 511 of the MEFV protein (p.Ala511Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs144270019, ExAC 0.007%). This variant has been observed in an individual affected with familial mediterranean fever (PMID: 22281876). 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.
Mendelics RCV000801307 SCV001139849 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193207 SCV001361913 uncertain significance not specified 2019-08-15 criteria provided, single submitter clinical testing Variant summary: MEFV c.1532C>T (p.Ala511Val) 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 4e-05 in 251462 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (4e-05 vs 0.022), allowing no conclusion about variant significance. The variant, c.1532C>T, has been reported in the literature in individuals affected with Familial Mediterranean Fever (Akar_2010, Vergara_2012). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

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