Submissions for variant NM_000243.3(MEFV):c.1223G>A (p.Arg408Gln)

gnomAD frequency: 0.01456  dbSNP: rs11466024

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000224408	SCV000279047	likely benign	not provided	2023-03-10	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224408	SCV000281405	likely benign	not provided	2015-06-02	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
PreventionGenetics, part of Exact Sciences	RCV000218029	SCV000303116	benign	not specified		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224408	SCV000493147	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224408	SCV000604176	benign	not provided	2023-11-17	criteria provided, single submitter	clinical testing
Invitae	RCV000002661	SCV000629018	likely benign	Familial Mediterranean fever	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000218029	SCV000696042	likely benign	not specified	2022-02-23	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.1223G>A (p.Arg408Gln) results in a conservative amino acid change located in the B-box-type zinc finger (IPR000315) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. A recent report utilizing the meta predictor tool, REVEL (Rare Exome Variant Ensemble Learner) to assess the pathogenicity of MEFV variants with ambiguous classification proposed a likely benign outcome for this variant (Accetturo_2019). In this study, REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Auto Inflammatory Diseases. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in MEFV causing Familial Mediterranean Fever phenotype (0.022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. When examined across all populations represented in the gnomAD database, the variant did not exceed the estimated maximal expected allele frequency for a disease causing MEFV allele however, in the European sub-cohort, 20 homozygous occurrences were observed, suggesting a benign nature for the variant across ethnicities. c.1223G>A has been extensively reported in databases and in the literature in individuals affected with Familial Mediterranean Fever or unexplained fevers, frequently as part of a haplotype with p.P369S (example, Ryan_2010, Migita_2014, Stoffels_2014, Pieri_2015, Hageman_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. This haplotype has been reported in the homozygous state in controls as well (3 occurrences in 1000G) supporting the neutral nature of the complex allele. In two families (Feng 2009), the variant or its complex with P369S was shown to not co-segregate in all affected family members. The complex variant was also found in compound heterozygous state with a known pathogenic variant in unaffected parents (Moussa_2013). At-least one functional study further supports a neutral nature for the variant. This substitution is located in exon 3 encoding a B-box domain and is necessary for interactions with proline serine threonine phosphatase interacting protein 1 (PSTPIP1) (Ryan_2010). The ability of the MEFV to bind PSTPIP1 was not affected by the variant in isolation or as a part of a complex allele. Additionally, in silico structural modeling predicted that the variant does not result in alteration to the secondary structure elements potentially required to maintain the structural integrity of the B-box domain (Ryan_2010). Multiple clinical diagnostic laboratories and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. These submitters have reported the variant with conflicting assessments ranging from Likely Benign (n=3), Uncertain Significance (n=5), Likely Pathogenic (n=2) to Pathogenic (n=1). Of note, one of these submitters has recently re-evaluated this variant from Likely Pathogenic to a VUS but not updated their ClinVar record. We have considered their assessment as a VUS in this context. Some submitters have provided overlapping evidence utilized in the context of our evaluation. We have followed this variant for over four years and previously classified it as a VUS-possibly benign variant. In our review of published evidence spanning over 20 years (1999-2019), the majority of evidence appears to point toward a non-pathogenic outcome however more data is required to conclusively determine the clinical consequences of this variant. Therefore, based on the evidence outlined above, this variant in isolation retains its classification as likely benign.
Illumina Laboratory Services, Illumina	RCV000002661	SCV001277732	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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000224408	SCV001450349	uncertain significance	not provided	2024-01-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000002661	SCV001623488	uncertain significance	Familial Mediterranean fever	2021-05-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000224408	SCV001712844	uncertain significance	not provided	2020-09-10	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262551	SCV002543693	uncertain significance	Autoinflammatory syndrome	2022-04-04	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000002661	SCV002580762	uncertain significance	Familial Mediterranean fever	2022-03-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362552	SCV002656578	uncertain significance	Inborn genetic diseases	2017-03-11	criteria provided, single submitter	clinical testing	The p.R408Q variant (also known as c.1223G>A), located in coding exon 3 of the MEFV gene, results from a G to A substitution at nucleotide position 1223. The arginine at codon 408 is replaced by glutamine, an amino acid with highly similar properties. This variant is often seen in cis with p.P369S, and has been identified in individuals with typical and atypical familial Mediterranean fever (FMF) as well as in healthy controls (Cazeneuve C et al. Am. J. Hum. Genet., 1999 Jul;65:88-97; Feng J et al. PLoS ONE, 2009 Dec;4:e8480; Ryan JG et al. Ann. Rheum. Dis., 2010 Jul;69:1383-8; Migita K et al. Medicine (Baltimore), 2014 May;93:158-64). The p.P369S and p.R408Q variants were found to be in strong linkage disequilibrium; genetic and functional data suggest that the p.[P369S; R408Q] complex allele is unlikely to represent a classic FMF disease-associated mutation, and is more likely to be a high frequency low-penetrance mutation (Ryan JG et al. Ann. Rheum. Dis., 2010 Jul;69:1383-8; Migita K et al. Medicine (Baltimore), 2014 May;93:158-64). Based on data from ExAC, the A allele has an overall frequency of approximately 1.304% (1375/105484) total alleles studied. The highest observed frequency was 5.315% (418/7864) of East Asian alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence to date, the clinical significance of this alteration remains unclear (Ryan et al. Rheum Dis. 2010;69(7):1383-8).
Revvity Omics, Revvity	RCV000224408	SCV003810939	uncertain significance	not provided	2023-04-21	criteria provided, single submitter	clinical testing
OMIM	RCV000002661	SCV000022819	uncertain significance	Familial Mediterranean fever	2013-01-01	no assertion criteria provided	literature only
Eurofins Ntd Llc (ga)	RCV000224408	SCV000228829	likely pathogenic	not provided	2017-09-21	flagged submission	clinical testing
GeneReviews	RCV000002661	SCV000484961	not provided	Familial Mediterranean fever		no assertion provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000224408	SCV001550949	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MEFV p.Arg408Gln variant is a well-studied variant in association with Familial Mediterranean Fever (FMF) and has been identified in 159 of 8198 proband chromosomes from multiple patients with the FMF phenotype (freq=0.019), however the role of this variant in disease is unclear (Cazeneuve_1999_PMID:10364520; Bonyadi_2009_PMID: 19863562; Migita_2014_PMID:24797171; Tsuchiya-Suzuki_2009_PMID:19531756; Migita_2012_PMID:22467954; De Pieri_2015_PMID:25866490; Lainka_2012_PMID:22903357; Berdeli_2011_PMID:21413889; Migita_2016_PMID:27473114). The variant was reported in dbSNP (ID: rs11466024), LOVD 3.0 and ClinVar (classified in relation to FMF as benign [Prevention Genetics, 2017], likely benign [Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, 2015], Likely pathogenic [EGL Genetic Diagnostics, 2017], Pathogenic [GeneReviews, 2016], Uncertain significance [GeneDx 2017; Praxis fuer Humar 2016; Invitae 2018; Integrated Genetics/Laboratory Corporation of America 2016; OMIM 2013; Integrated Genetics/Laboratory Corporation of America 2015]). The variant was not identified in the Cosmic database. The variant was identified in control databases in 3771 of 282186 chromosomes (53 homozygous) at a frequency of 0.013364 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 1072 of 19934 chromosomes (freq: 0.05378), Ashkenazi Jewish in 301 of 10342 chromosomes (freq: 0.0291), South Asian in 455 of 30606 chromosomes (freq: 0.01487), European (Finnish) in 363 of 25074 chromosomes (freq: 0.01448), Other in 94 of 7204 chromosomes (freq: 0.01305), European (non-Finnish) in 1175 of 128692 chromosomes (freq: 0.00913), Latino in 208 of 35416 chromosomes (freq: 0.005873), and African in 103 of 24918 chromosomes (freq: 0.004134). The R408Q variant is often found as a complex allele with the MEFV P369S variant. Bonyadi et al. (2009) identified the R408Q variant in 7/524 Azeri Turkish FMF patients as a complex allele with P369S; 4 of these patients were also compound heterozygous for another MEFV variant (Bonyadi_2009_PMID: 19863562). Migita et al. (2014) also identified the variant as a complex allele with P369S variant in 9/178 patients with typical FMF and 28/133 patients with atypical FMF; in 8 of these typical FMF and 15 of these atypical FMF patients the variant was present in the compound heterozygous state with at least one other MEFV variant (Migita_2014_PMID:24797171). A family with a severe autoinflammatory phenotype underwent testing of a 120 gene inflammasome-related panel which revealed a P369S/R408Q complex allele in the MEFV gene inherited from the father and found in both affected children as well as a T577A in the MEFV gene inherited from the affected mother and also found in both affected children (Stoffels_2014_PMID:23505238). Ryan et al. (2010) identified 35/40 symptomatic and 4 asymptomatic FMF family members with the R408Q/P369S complex allele. Functional studies of these variants did not demonstrate a significant difference from the wildtype in the ability of pyrin to bind to PSTPIP1, therefore the role of these variants in FMF and their potential functional impact is not known (Ryan_2010_PMID: 19934105). The variant occurs outside of the splicing consensus sequence however 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) predict the creation of a new 5’ splice site. The p.Arg408 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance, although we would suggest that this variant may be a low penetrant allele that can contribute to FMF in an autosomal recessive manner.