ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.1223G>A (rs11466024)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000224408 SCV000228829 likely pathogenic not provided 2017-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000218029 SCV000279047 uncertain significance not specified 2017-06-13 criteria provided, single submitter clinical testing R408Q is a variant of uncertain significance that has been described only rarely in affected individuals of Armenian descent, and nearly always in cis phase with the P369S variant (Cazeneuve, 1999). The R408Q variant is observed in 55/1008 (5.46%) alleles from individuals of East Asian background, in the ExAC dataset and the 1000 Genomes Project (Lek et al., 2016; 1000 Genomes Consortium et al., 2015). Although this variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, it occurs at a position that is not conserved. Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
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,PreventionGenetics RCV000218029 SCV000303116 benign not specified criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224408 SCV000493147 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000224408 SCV000604176 uncertain significance not provided 2017-06-06 criteria provided, single submitter clinical testing
Invitae RCV000002661 SCV000629018 likely benign Familial Mediterranean fever 2020-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 408 of the MEFV protein (p.Arg408Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs11466024, gnomAD 5%), including 53 homozygous individuals. This variant has been reported on the same chromosome (in cis) with MEFV p.Pro369Ser in many individuals affected with MEFV-related disease and is associated with highly variable phenotypes (PMID: 10364520, 19934105, 24797171, Invitae). Disease co-segregation in multiple families has been suggested (PMID: 19934105). However, many studies of this variant have small sample sizes and/or only examine selected exons or variants in the MEFV gene. Clinvar contains an entry for this variant (Variation ID: 2552). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, Polyphen-2, Align-GVGD) all suggest that the variant is likely to be tolerated. Experimental evidence also supports that this variant does not interfere with the interaction between the encoded protein pyrin and its partner PSTPIP1 protein (PMID: 19934105). In summary, while this variant has been reported in the literature in many individuals affected with FMF, it is observed in a high frequency in population databases. Experimental evidence suggests that this variant does not affect protein function. Based on the available evidence it has been classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000218029 SCV000696042 likely benign not specified 2021-02-16 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). Eight 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=2), Uncertain Significance (n=5), Likely Pathogenic (n=1) 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 Clinical Services Laboratory,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 Karolinska University Hospital,Karolinska University Hospital RCV000224408 SCV001450349 likely pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing
Nilou-Genome 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
OMIM RCV000002661 SCV000022819 uncertain significance Familial Mediterranean fever 2013-01-01 no assertion criteria provided literature only
GeneReviews RCV000002661 SCV000484961 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria 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.

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