ClinVar Genomic variation as it relates to human health

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.

See Variant Classification Assertion Criteria.

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). Fourteen ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=11), likely benign (n=2) or likely 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 classified as likely benign.

The p.P369S variant (also known as c.1105C>T), located in coding exon 3 of the MEFV gene, results from a C to T substitution at nucleotide position 1105. The proline at codon 369 is replaced by serine, an amino acid with similar properties. This variant is often seen in cis with p.R408Q, and has been identified in individuals with typical and atypical familial Mediterranean fever (FMF) as well as in healthy controls (Aksentijevich I et al. Am. J. Hum. Genet., 1999 Apr;64:949-62; Cazeneuve C et al. Am. J. Hum. Genet., 1999 Jul;65:88-97; Feng J et al. PLoS ONE, 2009 Dec;4:e8480; Ryan JG et al. Ann. Rheum. Dis., 2010 Jul;69:1383-8; Migita K et al. Medicine (Baltimore), 2014 May;93:158-64). The p.P369S and p.R408Q variants were found to be in strong linkage disequilibrium; genetic and functional data suggest that the p.[P369S; R408Q] complex allele is unlikely to represent a classic FMF disease-associated mutation, and is more likely to be a high frequency low-penetrance mutation (Ryan JG et al. Ann. Rheum. Dis., 2010 Jul;69:1383-8; Migita K et al. Medicine (Baltimore), 2014 May;93:158-64). Based on data from ExAC, the T allele has an overall frequency of approximately 1.437% (1518/105622) total alleles studied. The highest observed frequency was 7.026% (550/7828) of East Asian alleles. This amino acid position is well conserved in limited vertebrate species; however, serine is the reference amino acid is several species. In addition, this alteration is predicted to be possibly damaging by PolyPhen but tolerated by SIFT in silico analyses. Based on the available evidence to date, the clinical significance of this alteration remains unclear (Ryan JG et al. Ann. Rheum. Dis., 2010 Jul;69:1383-8).

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.