ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1105C>T (p.Pro369Ser) (rs11466023)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000215679 SCV000604177 uncertain significance not specified 2017-06-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416092 SCV000493148 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000416092 SCV000228830 likely pathogenic not provided 2014-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000215679 SCV000279046 uncertain significance not specified 2017-06-13 criteria provided, single submitter clinical testing P369S occurs on approximately 2-3% of MEFV genes carrying pathogenic variants. This variant has been described in individuals of Armenian and Ashkenazi Jewish ancestry, as well as other ethnicities (Aksentijevich et al., 1999). It was considered a low penetrance pathogenic variant and has occasionally been observed in a homozygous state in clinically unaffected Ashkenazi Jewish individuals. It was also observed with an allele frequency of 1% in the general population and may be a functional polymorphism (Masters et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
GeneReviews RCV000002660 SCV000484960 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000002660 SCV000052828 uncertain significance Familial Mediterranean fever 2015-10-05 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000416092 SCV000696040 uncertain significance not provided 2017-08-10 criteria provided, single submitter clinical testing Variant summary: The MEFV c.1105C>T (p.Pro369Ser) variant involves the alteration of a non-conserved nucleotide, which 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 4148/279094 control chromosomes (90 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.072171 (1361/18858). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In two families with this variant (one with dominant FMF and another with FMF and Hyper IgD syndrome), another variant or genotype fully explained the phenotypes, suggesting this variant has a possible benign outcome. In silico modelling suggests the variant doesnt result in significant alteration in secondary structure elements potentially required to maintain the structural integrity. Coimmunoprecipitation studies confirm that variant doesnt affect pyrin's binding to WT or proline serine threonine phosphatase interacting protein 1 (PSTPIP1) (Ryan_2010). Multiple clinical diagnostic laboratories have cited the variant with conflicting classifications, pathogenic/likely pathogenic, uncertain significance, or benign. Combining all information together, 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 RCV000002660 SCV000629016 uncertain significance Familial Mediterranean fever 2018-01-24 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 369 of the MEFV protein (p.Pro369Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs11466023, ExAC 7%), including 38 homozygous individuals. This variant has been reported as in cis with MEFV p.Arg408Gln 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). This variant has also been observed as heterozygous or in combination with other MEFV variants in affected individuals (PMID: 26027984, 25708585, 19934105). ClinVar contains an entry for this variant (Variation ID: 2551). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental evidence indicates 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 RCV000002660 SCV000022818 uncertain significance Familial Mediterranean fever 2013-01-01 no assertion criteria provided literature only
PreventionGenetics RCV000215679 SCV000303115 benign not specified criteria provided, single submitter clinical testing

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