ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.926C>T (p.Thr309Met) (rs104895155)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001719850 SCV000279043 likely benign not provided 2018-03-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24233262, 29159471)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000214115 SCV000696082 uncertain significance not specified 2019-12-13 criteria provided, single submitter clinical testing Variant summary: MEFV c.926C>T (p.Thr309Met) 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 0.00057 in 247628 control chromosomes, predominantly at a frequency of 0.0028 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00057 vs 0.022), allowing no conclusion about variant significance. c.926C>T has been reported in the literature in patients affected with Familial Mediterranean Fever (Chandrakasan_2014), unclassified mongenic auto inflammtory disease (Omoyinmi_2017) and adult onset Still's disease (Sighart_2017) . These reports however, 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. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000083806 SCV001019961 likely benign Familial Mediterranean fever 2020-11-02 criteria provided, single submitter clinical testing
Mendelics RCV000083806 SCV001139865 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285701 SCV001472177 uncertain significance none provided 2020-08-26 criteria provided, single submitter clinical testing The MEFV c.926C>T; p.Thr309Met variant (rs104895155) is reported in the literature in several individuals affected with periodic fever syndromes (Chandrakasan 2014, Infevers database). This variant is found in the South Asian population with an overall allele frequency of 0.28% (85/30576 alleles, including one homozygote) in the Genome Aggregation Database. The threonine at codon 309 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Thr309Met variant is uncertain at this time. References: Infevers database: https://infevers.umai-montpellier.fr/web/search.php?n=1 Chandrakasan S et al. Clinical and genetic profile of children with periodic fever syndromes from a single medical center in South East Michigan. J Clin Immunol. 2014 Jan;34(1):104-13.
Nilou-Genome Lab RCV000083806 SCV001712289 uncertain significance Familial Mediterranean fever 2021-05-18 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083806 SCV000115906 not provided Familial Mediterranean fever no assertion provided not provided

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