ClinVar Miner

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

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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 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.
PreventionGenetics,PreventionGenetics RCV000215679 SCV000303115 benign not specified 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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000215679 SCV000604177 uncertain significance not specified 2017-06-08 criteria provided, single submitter clinical testing
Invitae RCV000002660 SCV000629016 likely benign Familial Mediterranean fever 2020-01-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000215679 SCV000696040 uncertain significance not specified 2019-05-16 criteria provided, single submitter clinical testing Variant summary: MEFV c.1105C>T (p.Pro369Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.015 in 250836 control chromosomes in the gnomAD database (exome dataset), including 75 homozygotes. The variant was observed predominantly within the East Asian subpopulation at a frequency of 0.07, that is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MEFV causing Familial Mediterranean Fever (FMF) phenotype (0.022), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Additionally, the variant was found with even higher frequencies in the 1000 Genomes Project within some East Asian subpopulations, further supporting that this variant is likely a benign polymorphism (Moradian 2017). The variant, c.1105C>T, has been reported in the literature in numerous individuals affected with FMF, generally in combination with one or more other MEFV variants (e.g. Ryan_2010, Caglayan_2010, Berdeli_2011, Migita 2016, Hoang_2019). However, a recent study evaluating the prevalence of the disease in the Japanese population (Migita 2016) found no significant difference in allele frequencies between FMF patients (8.6%; 33/384 alleles) and healthy subjects (6.2%; 13/210 alleles). The variant was reported in a family in two asymptomatic individuals with another pathogenic MEFV variant (c.1437C>G (p.Phe479Leu) or c.2040G>C (p.Met680Ile)) in trans (Moussa_2013), providing supporting evidence for a benign role. Co-immunoprecipitation studies demonstrated that the variant does not affect the binding of pyrin to the PSTPIP1 protein (Ryan_2010). Five other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, without evidence for independent evaluation, and classified the variant as pathogenic (1x) or VUS (4x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000416092 SCV001134276 uncertain significance not provided 2019-02-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002660 SCV001279954 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 RCV000002660 SCV000022818 uncertain significance Familial Mediterranean fever 2013-01-01 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
GeneReviews RCV000002660 SCV000484960 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only

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