Submissions for variant NM_000243.3(MEFV):c.2338C>A (p.Pro780Thr)

gnomAD frequency: 0.00001  dbSNP: rs104895154

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000217446	SCV000279570	uncertain significance	not provided	2022-04-28	criteria provided, single submitter	clinical testing	Identified in the literature (Goulielmos et al., 2006) to be associated with mild severity of familial Mediterranean fever; however, clinical information was not provided; Identified in a patient with palindromic rheumatism in the literature (Canete et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17665427, 16730661)
Blueprint Genetics	RCV000217446	SCV000927692	uncertain significance	not provided	2018-05-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000083763	SCV001139802	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000083763	SCV001217160	uncertain significance	Familial Mediterranean fever	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 780 of the MEFV protein (p.Pro780Thr). This variant is present in population databases (rs104895154, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of MEFV-related conditions (PMID: 16730661, 17665427). ClinVar contains an entry for this variant (Variation ID: 97511). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The threonine 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.
Illumina Laboratory Services, Illumina	RCV000083763	SCV001277618	uncertain significance	Familial Mediterranean fever	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262642	SCV002543746	uncertain significance	Autoinflammatory syndrome	2021-02-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298469	SCV002598584	uncertain significance	not specified	2022-09-14	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.2338C>A (p.Pro780Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2338C>A has been reported in the literature in individuals affected with Familial Mediterranean Fever (example, Gouliemos_2006, Canete_2007). These report(s) 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. 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	RCV000083763	SCV003802156	benign	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126467	SCV003802167	benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126468	SCV003802178	benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083763	SCV000115859	not provided	Familial Mediterranean fever		no assertion provided	not provided
Natera, Inc.	RCV000083763	SCV001462090	uncertain significance	Familial Mediterranean fever	2020-09-16	no assertion criteria provided	clinical testing