ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.1105C>T (rs11466023)

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Total submissions: 16
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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 2020-12-03 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, gnomAD 7%) including 86 homozygotes. This variant has been reported on the same chromosome (in cis) with MEFV p.Arg408Gln in many individuals affected with familial mediteranean fever (FMF) and is associated with highly variable phenotypes (PMID: 10364520, 19934105, 2479171, Invitae). Disease co-segregation in multiple families has been suggested (PMID: 26027984, 25708585, 19934105). However, many studies of this variant have small sample sizes and/or only examine selected exons or variants in the MEFV gene. In one study, this variant was more frequent in healthy individuals compared to those with a clinical diagnosis of FMF (PMID: 23907647). ClinVar contains an entry for this variant (Variation ID: 2551). Experimental evidence indicates that this variant does not interfere with the interaction between the encoded protein pyrin and its partner PSTPIP1 protein (PMID: 19934105). An ex vivo colchicine functional assay showed that the functional response in patients with this variant was similar to healthy controls (PMID: 32312770). 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 and healthy controls. 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 RCV000215679 SCV000696040 likely benign not specified 2020-10-03 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 253268 control chromosomes, predominantly at a frequency of 0.07 within the East Asian subpopulation in the gnomAD database, including 54 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 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. 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). Due to its high frequency, the variant, c.1105C>T, has been reported in the literature in sequencing studies of 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). Many of the earlier reports suffer from a lack of extensive genotyping limited to small panels of variants in the MEFV gene. 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). Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5), likely benign (n=1) or pathogenic (n =1). At-least one submitting clinical diagnostic laboratory has re-classified this variant as likely benign since its last evaluation by our laboratory. Some sumbitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely 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.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000416092 SCV001450348 likely pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000416092 SCV001712845 uncertain significance not provided 2020-09-10 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000002660 SCV001737361 uncertain significance Familial Mediterranean fever 2021-06-10 criteria provided, single submitter clinical testing
OMIM RCV000002660 SCV000022818 uncertain significance Familial Mediterranean fever 2013-01-01 no assertion criteria provided literature only
GeneReviews RCV000002660 SCV000484960 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Natera, Inc. RCV000002660 SCV001462420 uncertain significance Familial Mediterranean fever 2020-01-06 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000416092 SCV001551664 uncertain significance not provided no assertion criteria provided clinical testing The MEFV p.Pro369Ser variant a well-studied variant in association with Familial Mediterranean Fever (FMF) and has been identified in 104 of 5484 proband chromosomes from multiple patients with the FMF phenotype (freq=0.019), however the role of this variant in disease is unclear (Migita_2014_PMID:24797171; Cazeneuve_1999_PMID:10364520; Aksentijevich_1999_PMID:10090880; Caglayan_2010_PMID:19934083; Migita_2012_PMID:22467954; Berdeli_2011_PMID:21413889). The variant was also identified in dbSNP (ID: rs11466023), LOVD 3.0 and ClinVar (classified in relation to FMF as benign [Prevention Genetics], likely pathogenic ([EGL Genetic Diagnostics, 2014], pathogenic [GeneReviews, 2016],  Uncertain significance [OMIM 2013; Integrated Genetics/Laboratory Corporation of America 2015; Integrated Genetics/Laboratory Corporation of America 2017; Invitae 2018; ARUP Laboratories 2017; GeneDx 2017; Praxis fuer Humangenetik Tuebingen 2016]). The variant was not identified in the Cosmic database. The variant was identified in control databases in 4150 of 282228 chromosomes (86 homozygous) at a frequency of 0.014704 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 1425 of 19936 chromosomes (freq: 0.07148), Ashkenazi Jewish in 302 of 10358 chromosomes (freq: 0.02916), South Asian in 472 of 30616 chromosomes (freq: 0.01542), European (Finnish) in 363 of 25100 chromosomes (freq: 0.01446), Other in 96 of 7214 chromosomes (freq: 0.01331), European (non-Finnish) in 1178 of 128636 chromosomes (freq: 0.009158), Latino in 213 of 35426 chromosomes (freq: 0.006013), and African in 101 of 24942 chromosomes (freq: 0.004049). The P369S variant is often found as a complex allele with the MEFV R408Q variant. Bonyadi et al. (2009) identified the P369 variant in 7/524 Azeri Turkish FMF patients as a complex allele with R408Q; 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 R408Q 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). Ryan et al. (2010) identified 35/40 symptomatic and 4 asymptomatic FMF family members with the R408Q/P369S complex allele, with the other 5/40 symptomatic family members only having the P369S variant. 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). There are also multiple case reports in which patients with atypical or late onset FMF are found to have the p.Pro369Ser variant along with other MEFV variants (Kitade_2015_PMID:26027984; Yamagami_2017_PMID:28001092). Hannan et al reported an atypical case of FMF with a late onset of attacks who was found to have the P369S/R408Q complex allele as well as the E148Q MEFV variant; this suggests a highly variable clinical phenotype of FMF (Hannan_2012_PMID:22906030). The p.Pro369 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 and contribute to FMF in an autosomal recessive manner.

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