ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.866C>T (p.Ala289Val)

gnomAD frequency: 0.00006  dbSNP: rs104895132
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000594000 SCV000702665 uncertain significance not provided 2016-11-15 criteria provided, single submitter clinical testing
Mendelics RCV000083802 SCV001139867 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000083802 SCV001418589 uncertain significance Familial Mediterranean fever 2022-10-24 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 289 of the MEFV protein (p.Ala289Val). This variant is present in population databases (rs104895132, gnomAD 0.02%). This missense change has been observed in individual(s) with MEFV-related conditions (PMID: 20041150, 25821352). ClinVar contains an entry for this variant (Variation ID: 97550). 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, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx RCV000594000 SCV002005213 uncertain significance not provided 2023-08-02 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17665448, 26984802, 19790133, no PMID, 20041150, 25821352, 34426522, 35358658, 31512232)
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002262656 SCV002542310 uncertain significance Autoinflammatory syndrome 2021-04-30 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002483165 SCV002781247 uncertain significance Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis 2022-04-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003114248 SCV003800685 uncertain significance not specified 2023-01-04 criteria provided, single submitter clinical testing Variant summary: MEFV c.866C>T (p.Ala289Val) 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 0.00012 in 251310 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00012 vs 0.022), allowing no conclusion about variant significance. c.866C>T has been reported in the literature in individuals affected with Familial Mediterranean Fever, Periodic Syndrome and Stills disease who carried the variant in the heterozygous state, with no second allele reported (Feng_2009, Perko_2015, Sighart_2018, Rostmaizadeh_2019). Additionally, the variant was reported as a de novo mutation in a heterozygous patient with recurrent attacks of fever, abdominal pain, vomiting, constipation and oral aphthosis (Kosukcu_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab RCV000083802 SCV003802247 likely benign Familial Mediterranean fever 2023-02-08 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003126493 SCV003802248 benign Familial Mediterranean fever, autosomal dominant 2023-02-08 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003126494 SCV003802249 benign Acute febrile neutrophilic dermatosis 2023-02-08 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083802 SCV000115901 not provided Familial Mediterranean fever no assertion provided not provided
Natera, Inc. RCV000083802 SCV002087428 uncertain significance Familial Mediterranean fever 2020-03-30 no assertion criteria provided clinical testing

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