Submissions for variant NM_000243.3(MEFV):c.1437C>G (p.Phe479Leu)

dbSNP: rs104895083

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508324	SCV000604190	pathogenic	not provided	2020-08-25	criteria provided, single submitter	clinical testing	The MEFV c.[501G>C;1437C>G]; p.[Glu167Asp;Phe479Leu] variant is a complex allele consisting of two changes on the same chromosome, p.Glu167Asp and p.Phe479Leu. Although p.Phe479Leu has been reported on its own, to the best of our knowledge p.Glu167Asp has only been reported as a complex allele with p.Phe479Leu. The complex variant has been published in the literature in both the homozygous and compound heterozygous state in individuals affected with familial Mediterranean fever (Bernot 1998, Bonyadi 2009, Mansour 2001, Neocleous 2015) and is one of the most common pathogenic MEFV variants in the Cypriot populations (Neocleous 2015). Based on available information, this variant is considered to be pathogenic. References: Bernot A et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. Bonyadi M et al. MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever. Clin Genet. 2009 Nov;76(5):477-80. Mansour I et al. Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations. Eur J Hum Genet. 2001 Jan;9(1):51-5. Neocleous V et al. Familial Mediterranean fever associated with MEFV mutations in a large cohort of Cypriot patients. Ann Hum Genet. 2015 Jan;79(1):20-7
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508324	SCV001134277	pathogenic	not provided	2019-02-20	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/282890 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Statistically enriched in patients compared to ethnically matched controls.
Mendelics	RCV000002654	SCV001139854	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000508324	SCV001245674	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000002654	SCV001416538	uncertain significance	Familial Mediterranean fever	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 479 of the MEFV protein (p.Phe479Leu). This variant is present in population databases (rs104895083, gnomAD 0.009%). This variant has been observed frequently in cis (on the same chromosome) with the MEFV p.Glu167Asp variant in individuals with MEFV-related disorders with variable phenotypes and a wide range of severity (including asymptomatic individuals) (PMID: 9668175, 11175300, 25708585, 25393764, 22975760, 23907647, 26351556, 29363386, 29178647). In some of these individuals, an additional MEFV variant was not identified on the opposite allele, while in others, multiple additional MEFV variants were identified. Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 2545). 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 leucine 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.
Hadassah Hebrew University Medical Center	RCV000002654	SCV001437668	pathogenic	Familial Mediterranean fever	2019-06-20	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000508324	SCV001449673	likely pathogenic	not provided	2017-01-11	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262545	SCV002543706	likely pathogenic	Autoinflammatory syndrome	2021-09-03	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000002654	SCV002580638	likely pathogenic	Familial Mediterranean fever	2022-03-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230343	SCV003928874	uncertain significance	not specified	2023-04-06	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.1437C>G (p.Phe479Leu) 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 4e-05 in 251496 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (4e-05 vs 0.022), allowing no conclusion about variant significance. c.1437C>G has been widely reported in the literature in individuals affected with Familial Mediterranean Fever. It is often reported in the same chromosome (in cis) with c.501G>C (p.Glu167Asp) in many studies. However, the limited extent of genotyping or unclear specification of phase preclude a traceable association of this specific variant in isolation to the phenotype of Familial Mediterranean Fever (example, PMID: 15951859, 31598713, 31989427, 9668175, 35098403, 29040788, 19253030, 20485448, 15146467, 25393764, 34328662, 17566872, 33726481, 31646357). 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. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=8; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003466786	SCV004194410	pathogenic	Familial Mediterranean fever, autosomal dominant	2023-10-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000002654	SCV004847509	pathogenic	Familial Mediterranean fever	2022-06-23	criteria provided, single submitter	clinical testing	The p.Phe479Leu variant is a well established pathogenic variant and it has been reported in the homozygous, heterozygous and compound heterozygous state (with other well known pathogenic MEFV variants) in numerous individuals with Familial mediteranean fever (FMF) (personal communication Pr Serge Amselem, Medlej-Hashim 2000 PMID: 10737992); frequently it has been reported in cis with p.Glu167Asp and this complex allele is one of the most common pathogenic MEFV variants in Cypriot populations (Neocleous 2015 PMID: 25393764 ). The p.Phe479Leu variant has been reported in ClinVar (Variation ID: 2545)and it has been identified in 4/68034 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive familial mediteranean fever (FMF). ACMG/AMP criteria applied: PM3_Very Strong, PM2_Supporting
OMIM	RCV000002654	SCV000022812	pathogenic	Familial Mediterranean fever	2009-11-01	no assertion criteria provided	literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000002654	SCV000115785	not provided	Familial Mediterranean fever		no assertion provided	not provided
Natera, Inc.	RCV000002654	SCV001452073	pathogenic	Familial Mediterranean fever	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000508324	SCV001741894	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000508324	SCV001927425	likely pathogenic	not provided		no assertion criteria provided	clinical testing