ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.910G>A (p.Gly304Arg) (rs75977701)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000030186 SCV000220948 likely benign Familial Mediterranean fever 2014-12-11 criteria provided, single submitter literature only
GeneDx RCV000414140 SCV000490612 likely pathogenic not provided 2016-03-14 criteria provided, single submitter clinical testing The c.910 G>A substitution in the MEFV gene has been reported in an individual with a suspected periodic fever syndrome. In addition, this substitution has been reported in the literature in a homozygous state in two individuals diagnosed with FMF (Tone et al., 2012). This nucleotide change occurs in the last base of exon 2, before the canonical GT splice site sequence in intron 2. As a result, this substitution destroys the splice donor site of intron 2, which is predicted to cause abnormal gene splicing. Tone et al. indicated that this mutation appears to cause increased production of an abnormal truncated protein product, which could disrupt normal function; therefore, c.910 G>A is a strong candidate as a disease-associated mutation. However, per the 1000 Genomes Project, this variant has been observed in ~1% of alleles from a control population; therefore, the possibility that it is a benign variant cannot be excluded.In approximately 30% of individuals with a clinical presentation and disease history consistent with FMF, only a single MEFV mutation can be identified.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508393 SCV000604170 uncertain significance not specified 2019-05-30 criteria provided, single submitter clinical testing The MEFV c.910G>A; p.Gly304Arg variant (rs75977701) is reported in the literature in individuals affected with atypical familial Mediterranean fever (Arasawa 2012, Gunesacar 2014, Kishida 2014, Migita 2014), but also in healthy controls (Migita 2012, Nonaka 2015, Oshima 2010, Taniuchi 2013). This variant is reported with conflicting interpretations of pathogenicity in ClinVar (Variation ID: 36513), and is found in the general population with an overall allele frequency of 0.47% (1318/281346 alleles, including 12 homozygotes), with an increased frequency in the Finnish European population of 2.7% (686/25046 alleles) in the Genome Aggregation Database. The glycine at codon 304 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, this variant resides in the last nucleotide of exon 2, and is predicted to disrupt the canonical splice donor site (Alamut v.2.11), with functional studies supporting a negative impact on gene function (Tone 2012). Due to conflicting information, the clinical significance of the p.Gly304Arg variant is uncertain at this time. References: Arasawa S et al. Mediterranean mimicker. Lancet. 2012 380(9858):2052. Gunesacar R et al. Frequency of MEFV gene mutations in Hatay province, Mediterranean region of Turkey and report of a novel missense mutation (I247V). Gene. 2014 546(2):195-9. Kishida D et al. Genotype-phenotype correlation in Japanese patients with familial Mediterranean fever: differences in genotype and clinical features between Japanese and Mediterranean populations. Arthritis Res Ther. 2014 16(5):439. Migita K et al. Clinical relevance of MEFV gene mutations in Japanese patients with unexplained fever. J Rheumatol. 2012 Apr;39(4):875-7. Migita K et al. Coexistence of familial Mediterranean fever and rheumatoid arthritis. Mod Rheumatol. 2014 24(1): 212-6. 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. Oshima K et al. A case of familial Mediterranean fever associated with compound heterozygosity for the pyrin variant L110P-E148Q/M680I in Japan. Mod Rheumatol. 2010 Apr;20(2):193-5. Taniuchi S et al. MEFV Variants in Patients with PFAPA Syndrome in Japan. Open Rheumatol J. 2013 7:22-5. Tone Y et al. Enhanced exon 2 skipping caused by c.910G>A variant and alternative splicing of MEFV genes in two independent cases of familial Mediterranean fever. Mod Rheumatol. 2012 22(1):45-51.
Integrated Genetics/Laboratory Corporation of America RCV000508393 SCV000696081 likely benign not specified 2019-01-25 criteria provided, single submitter clinical testing Variant summary: MEFV c.910G>A (p.Gly304Arg) 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. Although the variant causes a missense change, it is in the last nucleotide of the exon, which may also have an effect on normal splicing. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site and three predict it weakens a 5' donor site. These predictions are supported by at least one publication which demonstrated that the variant increases the in-frame skipping of exon 2 in patients' PBMCs, due to enhanced alternative splicing (Tone 2012). Authors transfected the normal and variant MEFV genes into HEK293T (embryonic kidney origin) cells, however the transfectants (i.e. both the full-length mutant containing the G304R missense change, and the exon 2 deleted short isoform) failed to show altered intracellular pyrin distribution in this cell type; as the cell system used by the authors may not represent a physiological cell type, the functional significance of this variant remains unclear at the cellular and/or organismal level. The variant allele was found at a frequency of 0.0047 in 282140 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.027 within the Finnish subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 1.25 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. Additionally, the variant was reported with even higher frequencies in the 1000 Genomes Project within some East Asian subpopulations, e.g. in Chinese Dai in Xishuangbanna (CDX) 5.4%, Han Chinese in Bejing (CHB) 2.4%, Japanese in Tokyo (JPT) 2.9%, Kinh in Ho Chi Minh City, Vietnam (KHV) 2.5%; suggesting this variant is likely a benign polymorphism (Moradian 2017). Though the variant, c.910G>A, has been reported in the literature in individuals affected with FMF, a recent study evaluating the prevalence of the disease in the Japanese population (Migita 2016) found similar allele frequencies among FMF patients (2.9%; 11/384 alleles) and healthy subjects (2.9%; 6/210 alleles); this frequency among healthy Japanese controls is comparable to that reported in large, Japanese control population databases (i.e. 2.46% in IJGVD, and 2% in HGVD). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, one laboratory classified the variant as benign, and a third laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000030186 SCV000753990 benign Familial Mediterranean fever 2019-12-31 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000030186 SCV000115903 not provided Familial Mediterranean fever no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.