Submissions for variant NM_000243.3(MEFV):c.501G>C (p.Glu167Asp)

gnomAD frequency: 0.00004  dbSNP: rs104895079

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588525	SCV000604193	uncertain significance	not provided	2022-02-04	criteria provided, single submitter	clinical testing	The MEFV c.501G>C; p.Glu167Asp variant (rs104895079) is reported in the homozygous and compound heterozygous state in affected individuals (Ceylan 2012, Papa 2017, Ustek 2008) and is often found on the same chromosome as c.1437C>G; p.Phe479Leu (Bernot 1998, Bonyadi 2009, Mansour 2001, Neocleous 2015). However, the c.1437C>G; p.Phe479Leu variant was not detected in this individual. The.501G>C; p.Glu167Asp variant was described as likely pathogenic by a panel of experts (Van Gijn 2018) and is listed in the ClinVar database (Variation ID: 2543). The variant is described in the general population with an overall allele frequency of 0.005% (10/213,066 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.535). Due to the uncertainty regarding the pathogenicity of the p.Glu167Asp variant when found individually, the clinical significance of the p.Glu167Asp variant is uncertain at this time. 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. Bozgeyik E et al. Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics. Genomics. 2020 Jul;112(4):2755-2762. Ceylan GG et al. Frequency of alterations in the MEFV gene and clinical signs in familial Mediterranean fever in Central Anatolia, Turkey. Genet Mol Res. 2012 May 7;11(2):1185-94. 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 Papa R et al A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. Orphanet J Rare Dis. 2017 Oct 18;12(1):167. Ustek D et al. MEFV gene 3'-UTR Alu repeat polymorphisms in patients with familial Mediterranean fever. Clin Exp Rheumatol. 2008 Jul-Aug;26(4 Suppl 50):S72-6. [OR] 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230342	SCV000696074	uncertain significance	not specified	2023-04-06	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.501G>C (p.Glu167Asp) results in a 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 4.4e-05 in 182315 control chromosomes (gnomAD, exomes dataset). c.501G>C (p.E167D) is often observed in the same chromosome (in cis) with c.1437C>G (p.Phe479Leu) forming a complex allele p.[E167D;F479L]. Nevertheless, E167D has also been reported in the literature as a variant in isolation in homozygous or compound heterozygous state, in a few individuals affected with Familial Mediterranean Fever (e.g. Ceylan_2012, Papa_2017, Ustek_2008, Bozgeyik_2020). These data indicate that the variant is likely to be associated with disease. In 2012, an international consortium of experts reached a consensus (as part of an agreed set of best practice guidelines) to test for 14 MEFV variants, nine of which were considered pathogenic (including E167D) and 5 of unknown significance (Shinar_2012). In addition, in 2018 the experts international study group for systemic autoinflammatory diseases (INSAID) agreed in a consensus classification of (provisional) likely pathogenic for the variant (Van Gijn_2018). 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 citing overlapping evidence utilized in the context of this evaluation (Pathogenic/Likely pathogenic, n=5; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mendelics	RCV000002652	SCV001139887	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588525	SCV001245677	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000002652	SCV001416539	uncertain significance	Familial Mediterranean fever	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 167 of the MEFV protein (p.Glu167Asp). This variant is present in population databases (rs104895079, gnomAD 0.01%). This variant has been observed frequently in cis (on the same chromosome) with the MEFV p.Phe479Leu variant in individuals with MEFV-related disorders with variable phenotypes and a wide range of severity (including asymptomatic individuals) (PMID: 9668175, 11175300, 12180071, 25708585, 25393764, 21413889, 26351556, 24469716, 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: 2543). ClinVar contains an entry for this variant (Variation ID: 2543). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262294	SCV001440108	uncertain significance	Familial Mediterranean fever, autosomal dominant	2019-01-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000588525	SCV001449672	likely pathogenic	not provided	2017-01-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000002652	SCV001653393	likely pathogenic	Familial Mediterranean fever	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000588525	SCV001813678	uncertain significance	not provided	2021-06-22	criteria provided, single submitter	clinical testing	Occurs often with the F479L variant, usually proven to be on the same allele (in cis) (Bernot A et al., 1998; Bozgeyik E et al., 2020; Bonyadi M et al., 2009; Ceylan GG et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25708585, 22614345, 9668175, 32199921, 19863562, 17489852, 24469716, 10090880, 29178647, 18609258, 15024744, 11175300, 25393764)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262543	SCV002543467	likely pathogenic	Autoinflammatory syndrome	2021-09-09	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000002652	SCV002580639	likely pathogenic	Familial Mediterranean fever	2022-03-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001262294	SCV004194419	uncertain significance	Familial Mediterranean fever, autosomal dominant	2022-10-24	criteria provided, single submitter	clinical testing
OMIM	RCV000002652	SCV000022810	pathogenic	Familial Mediterranean fever	2009-11-01	no assertion criteria provided	literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000002652	SCV000115875	not provided	Familial Mediterranean fever		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000588525	SCV001742805	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000588525	SCV001928982	pathogenic	not provided		no assertion criteria provided	clinical testing