Submissions for variant NM_000243.3(MEFV):c.926C>T (p.Thr309Met)

gnomAD frequency: 0.00032  dbSNP: rs104895155

Total submissions: 8

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	2024-01-29	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	RCV001719850	SCV001472177	uncertain significance	not 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.
Genome-Nilou Lab	RCV000083806	SCV001712289	uncertain significance	Familial Mediterranean fever	2021-05-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262657	SCV002542313	uncertain significance	Autoinflammatory syndrome	2021-11-26	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