ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1223G>A (p.Arg408Gln) (rs11466024)

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Total submissions: 12
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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 2020-01-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000218029 SCV000696042 likely benign not specified 2020-02-13 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 Autoinflammatory 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). Six 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=1), Uncertain Significance (n=4), Likely Pathogenic (n=1) to Pathogenic (n=1). 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 is re-classified 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.
OMIM RCV000002661 SCV000022819 uncertain significance Familial Mediterranean fever 2013-01-01 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000002661 SCV000052829 uncertain significance Familial Mediterranean fever 2015-10-05 no assertion criteria provided clinical testing
GeneReviews RCV000002661 SCV000484961 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only

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