ClinVar Genomic variation as it relates to human health

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 632 of the MEFV protein (p.Gly632Ser). This variant is present in population databases (rs104895128, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive MEFV-related conditions (PMID: 16730661, 17938136, 24469716, 25286988, 27310525, 27473114). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 97467). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: The MEFV c.1894G>A variant affects a non-conserved nucleotide, resulting in amino acid change from Gly to Ser. One structual study predicted this variant to be stabilizing (Arakelov_2015) and 3/4 in-silico tools predict this variant to be benign; however, functional studies have not been carried out to confirm these findings and in silico predictions are known to have low sensitivity and specificity for immunological gene variants. This variant is found in 5/122392 control chromosomes at a frequency of 0.0000409, which does not exceed the maximal expected frequency of a pathogenic allele (0.0216506) in this gene. No homozygotes have been reported in general population. The variant has been reported in at least eight FMF patients, one known to be compound heterozygous for a known pathogenic variant and three were homozygous for the variant. One family reported by Shinar_2007 also showed an indication that this variant cosegregated with disease. These patient data strongly suggests for a pathogenic outcome. This variant was also found in patients with adult-onset Stills disease and Behcet disease. The variant is considered a mild pathogenic mutation (Shinar_2007). Taken together, this variant has currently been classified as a Likely Pathogenic.

The MEFV c.1894G>A; p.Gly632Ser variant (rs104895128) is reported in the literature in multiple individuals affected with familial Mediterranean fever (Goulielmos 2006, Oztuzcu 2014, Shinar 2007, Umeda 2017) and in an individual with adult-onset Still’s disease (Nonaka 2015). This variant is also reported in ClinVar (Variation ID: 97467). This variant is found in the general population with an overall allele frequency of 0.004% (10/274946 alleles) in the Genome Aggregation Database. The glycine at codon 632 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.255). Due to limited information, the clinical significance of the p.Gly632Ser variant is uncertain at this time. References: Goulielmos GN et al. Mutational analysis of the PRYSPRY domain of pyrin and implications for familial mediterranean fever (FMF). Biochem Biophys Res Commun. 2006 Jul 14;345(4):1326-32. PMID: 16730661. Nonaka F et al. Increased prevalence of MEFV exon 10 variants in Japanese patients with adult-onset Still's disease. Clin Exp Immunol. 2015 Mar;179(3):392-7. PMID: 25286988. Oztuzcu S et al. Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep. 2014;41(4):2601-7. PMID: 24469716. Shinar Y et al. Unique spectrum of MEFV mutations in Iranian Jewish FMF patients--clinical and demographic significance. Rheumatology (Oxford). 2007 Nov;46(11):1718-22. PMID: 17938136. Umeda M et al. A Japanese familial Mediterranean fever patient with a rare G632S MEFV mutation in exon 10. Mod Rheumatol. 2017 Mar;27(2):378-379. PMID: 27310525.

MEFV NM_000243.2 exon 10 p.Gly632Ser (c.1894G>A): This variant has been reported in the literature in the heterozygous and compound heterozygous state in at least 3 individuals with Familial Mediterranean Fever (FMF), potentially segregating with disease in at least 2 affected family members (Shinar 2007 PMID:17938136). This variant has also been reported in at least 1 individual with adult onset Still's disease (Nonaka 2015 PMID:25286988, Umeda 2017 PMID:27310525). This variant is present in 0.001% (1/68022) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3243593-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:97467). This variant amino acid Serine (Ser) is present in >20 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

MEFV NM_000243.2 exon 10 p.Gly632Ser (c.1894G>A): This variant has been reported in the literature in the heterozygous and compound heterozygous state in at least 3 individuals with Familial Mediterranean Fever (FMF), potentially segregating with disease in at least 2 affected family members (Shinar 2007 PMID:17938136). This variant has also been reported in at least 1 individual with adult onset Still's disease (Nonaka 2015 PMID:25286988, Umeda 2017 PMID:27310525). This variant is present in 0.001% (1/68022) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3243593-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:97467). This variant amino acid Serine (Ser) is present in >20 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

The MEFV c.1894G>A variant is classified as a VUS (PS4_Supporting, PM2, PM3) The MEFV c.1894G>A variant is a single nucleotide change in exon 10/10 of the MEFV gene, which is predicted to change the amino acid glycine at position 632 in the protein to serine. The variant has been reported in patients with familial mediterranean fever, as heterozygous, compound heterozygous and homozygous (PMID:17938136, PMID:23137073, PMID:24469716) (PS4_Supporting, PM3). The variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het and 0 hom in 152182 sequenced alleles; highest frequency = 0.0014%, Non-Finnish European population) (PM2). The variant has been reported in dbSNP (rs104895128) and as disease causing in the HGMD database (CM0045304). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 97467). Another missense variant at the same amino acid location, p.Gly632Ala, has been reported on the HGMD database as disease causing (CM146757).

This sequence change is predicted to replace glycine with serine at codon 632 of the MEFV protein (p.(Gly632Ser)). The glycine residue is not conserved (100 vertebrates, UCSC), and is located in the B30.2/SPRY domain. There is a small physicochemical difference between glycine and serine. The variant is present in a large population cohort at a frequency of 0.004%, which is consistent with a recessive condition (10/274,946 alleles, 0 homozygotes in gnomAD v2.1). It has been identified heterozygous (alone), homozygous, and with a second MEFV allele in multiple cases with familial Mediterranean fever (FMF), and has been reported to segregate with disease dominantly in a single family with incomplete penetrance PMID: 17938136, 23137073, 24469716, 27310525). Multiple lines of computational evidence predict a benign effect for the missense substitution (6/6 algorithms). Another missense variant at this position (p.(Gly632Ala)) has been identified in Turkish FMF cases (PMID: 23862117, 33738724). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3_Strong, PM2_Supporting, BP4.