ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.436C>T (p.Gln146Ter) (rs876660990)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222115 SCV000279028 uncertain significance not provided 2015-02-13 criteria provided, single submitter clinical testing The Q146X variant of unknown significance in the MEFV gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, mutations in the MEFV gene resulting in the creation of a Stop codon are very rare, with only two reported to date (Notarnicola et al., 2001; Berdeli et al., 2011). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV000781527 SCV000919628 uncertain significance not specified 2018-10-18 criteria provided, single submitter clinical testing Variant summary: MEFV c.436C>T (p.Gln146X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 233434 control chromosomes (ExAC). To our knowledge, no occurrence of c.436C>T in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. However, HGMD cites two nonsense variants, p.Tyr471X and p.Tyr688X, downstream of this variant in affected individuals (Notarnicola_2011, Berdeli_2011). In addition, a ClinVar submssion from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, and considering that nonsense variants in this gene are very rare, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000818575 SCV000959195 uncertain significance Familial Mediterranean fever 2019-07-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln146*) in the MEFV gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MEFV-related conditions. ClinVar contains an entry for this variant (Variation ID: 234352). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MEFV cause disease. 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.

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