ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000224408 SCV000604176 uncertain significance not provided 2017-06-06 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
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.
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.
GeneReviews RCV000002661 SCV000484961 pathogenic Familial Mediterranean fever 2016-12-15 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
Integrated Genetics/Laboratory Corporation of America RCV000224408 SCV000696042 uncertain significance not provided 2016-12-19 criteria provided, single submitter clinical testing Variant summary: The variant affects a non-conserved nucleotide and results in a replacement of an Arginine (R) with a Glutamine (Q). 4/4 in silico tools predict neutral outcome for this change (SNPs&GO was not considered due to low reliability index). The variant was found in the East Asian subcohort of the ExAc project at an allele frequency of 5.4% which exceeds the expected maximal allele frequency of a disease causing MEFV allele indicating the variant to be a benign polymorphism in individuals of East-Asian origin. In other populations, the variant did not exceed the expected maximal allele frequency of a disease causing MEFV allele however, in the European subcohort, 10 homozygous occurrences were observed indicating a benign nature for the variant across ethnicities. This variant has been commonly reported in patients as part of a haplotype combination with other variant P369S. However, 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 was shown to not co-segregate in all affected family members. One functional study further supports a neutral nature for the variant. This substitution is located in exon 3 encoding a B-box domain 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). Considering all information, the variant is in the benign spectrum but more information is needed to classify it as a benign polymorphism; therefore it is classified as a variant of uncertain significance possibly benign until more information becomes available.
Invitae RCV000002661 SCV000629018 uncertain significance Familial Mediterranean fever 2018-01-24 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, ExAC 5%), including 25 homozygous individuals. This variant has been reported as in cis with MEFV p.Pro396Ser variant in many individuals affected with MEFV-related diseases and associated with highly variable phenotypes (PMID:10364520, 19934105, 24797171, Invitae). There is evidence of disease co-segregation in multiple families (PMID: 19934105).  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 this 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, this variant has been reported in many affected individuals and families as well as in the general population with no evidence of significant impact on protein function. However, the available evidence is currently insufficient to conclusively determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000002661 SCV000022819 uncertain significance Familial Mediterranean fever 2013-01-01 no assertion criteria provided literature only
PreventionGenetics RCV000218029 SCV000303116 benign not specified criteria provided, single submitter clinical testing

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