Submissions for variant NM_000243.3(MEFV):c.910G>A (p.Gly304Arg)

gnomAD frequency: 0.00316  dbSNP: rs75977701

Total submissions: 14

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	uncertain significance	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Reported in the presence of other MEFV variants in individuals with familial Mediterranean fever or unexplained fevers in published literature; however, many of these variants are of uncertain clinical significance (Migita et al., 2012; Kishida et al., 2014); Published functional studies suggest that variant alters gene splicing with skipping of exon 2, while the functional consequences of the resulting truncated protein product remain unknown and loss-of-function is not an established mechanism of disease (Tone et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in cis with a pathogenic MEFV variant in at least one family referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 28943464, 28863210, 32398039, 31401792, 23847694, 26933204, 23437051, 24965843, 24261781, 25525159, 21562927, 25671271, 24929125, 19967574, 23588594, 25261100, 23217869, 25286988, 25088882, 22467954, 25703702, 23137073, 30235678, 31155445, 31494649, 31682063, 32082075, 29178647, 31998953, 31989427, 31803701, 32824452, 31342094, 32115236, 33974187, Sargin[case report], 34177904, Tomokawa[other], 33733382, 34904166)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000414140	SCV000604170	uncertain significance	not provided	2023-04-20	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. Computational analyses predict that this variant is neutral (REVEL: 0.055). 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. PMID: 23217869. 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. PMID: 24929125. 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. PMID: 25261100. Migita K et al. Clinical relevance of MEFV gene mutations in Japanese patients with unexplained fever. J Rheumatol. 2012 Apr;39(4):875-7. PMID: 22467954. Migita K et al. Coexistence of familial Mediterranean fever and rheumatoid arthritis. Mod Rheumatol. 2014 24(1): 212-6. PMID: 24261781. 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. 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. PMID: 19967574. Taniuchi S et al. MEFV Variants in Patients with PFAPA Syndrome in Japan. Open Rheumatol J. 2013 7:22-5. PMID: 23847694. 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. PMID: 21562927.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000508393	SCV000696081	likely benign	not specified	2023-01-16	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. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant also alters a non-conserved nucleotide, positioned as the last nucleotide of exon 2 adjacent to the canonical splice donor site of intron 2. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing 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 0.0046 in 250756 control chromosomes, predominantly at a frequency of 0.018 within the East Asian subpopulation in the gnomAD database, including 12 homozygotes. 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 Beijing (CHB) 2.4%, Japanese in Tokyo (JPT) 2.9%, Kinh in Ho Chi Minh City in 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 Familial Mediterranean Fever (FMF) (example, Arasawa_2012, Comak_2013, Coskun_2015, Ebrahmi-Fakhari_2012, Fujikawa_2014, Gunesacar_2014, Jo_2015, Kishida_2014, Migita_2012, Migita_2014, Migita_2013, Oshima_2010, Tone_2012, Yoshioka_2014, Migita_2016, Moritake_2016, Erdem_2017, Ebadi_2017, Hara_2018, Dundar_2022), 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. 2.6% in jMorp, and 2% in HGVD). A functional study analyzed the effects of certain MEFV variants on cell death with or without stimulation with Clostridium difficile toxin A (TcdA) or UCN-01A and concluded that p.Gly304Arg conferred no substantial increase in cell death (Honda_2021). Additionally, in 2018 the experts international study group for systemic autoinflammatory diseases (INSAID) reported a validated classification of likely benign for the variant (Van Gijn_2018). One ClinVar submitter (evaluation after 2014) cites the variant as benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. At-least one submitter has re-classified this variant from a likely pathogenic to a VUS outcome since its previous evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV000030186	SCV000753990	benign	Familial Mediterranean fever	2024-01-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262592	SCV002543478	uncertain significance	Autoinflammatory syndrome	2020-04-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000414140	SCV003810943	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000414140	SCV003917471	benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	MEFV: PP3, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV004532422	SCV004754881	uncertain significance	MEFV-related disorder	2023-11-11	criteria provided, single submitter	clinical testing	The MEFV c.910G>A variant is predicted to result in the amino acid substitution p.Gly304Arg. This variant has been reported in patients with familial mediterranean fever (Tone et al. 2012. PubMed ID: 21562927; Ebadi et al. 2017. PubMed ID: 28943464) and in a patient with Sweets syndrome, myelodyplastic syndrome, high fever and leukocytosis (Jo et al. 2015. PubMed ID: 25671271). The c.910G>A substitution resides near the consensus intron 2 splice donor site and is predicted to abolish this splice donor site (Alamut v.2.11). Biochemical analysis in one report indicates that the c.910G>A substitution causes aberrant exon splicing and results in a truncated MEFV protein (Tone et al. 2012. PubMed ID: 21562927). This variant is also reported at a maximum allele frequency of 1.7% in East Asians and 2.75% in the Finnish population and has been reported in several individuals in the homozygous state in databases of apparently unaffected individuals (http://gnomad.broadinstitute.org/variant/16-3304158-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000030186	SCV004807293	uncertain significance	Familial Mediterranean fever	2024-03-26	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
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000414140	SCV001550841	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MEFV p.Gly304Arg variant has been reported many times in the literature in relation multiple phenotypes, mainly familial Mediterranean fever (FMF) or phenotypes involving reoccuring fevers, as well as rheumatic disease and other autoimmune phenotypes, however the variant has also been reported to a large extent in healthy control populations (Ebrahimi-Fakhari_2012_PMID: 23137073; Arasawa_2012_PMID: 23217869; Migita_2013_PMID: 23437051; Gunesacar_2014_PMID: 24929125; Yoshioka_2014_PMID: 25088882; Migita_2014_PMID: 24261781; Comak_2014_PMID: 23588594; Fujikawa_2014_PMID: 24965843; Jo_2015_PMID: 25671271; Moritake_2016_ PMID: 26933204; Nonaka_2015_PMID: 25286988; Taniuchi_2013_PMID: 23847694). The variant was identified in 11/384 alleles (freq=0.029) from patients with sure or probable FMF, 19/818 alleles (freq=0.023) from patients with unexplained fever but with an unlikely diagnosis of FMF and in 6/210 alleles (freq=0.029) from healthy controls (Migita_2016_PMID: 27473114). Another study identified the G304R variant in 2/116 patients with FMF as a complex compound heterozygous allele as these patients each carried two other MEFV variants (Kishida_2014_ PMID: 25261100). A study that performed mutational analysis of the MEFV gene on a patient with periodic fever and chest pain who was suspected to have FMF identified the G304R variant only in the patient's healthy mother and sister but not in the affected patient (Oshima_2009_19967574). However, a functional study identified two cases of FMF that were homozygous for the G304R variant and found that the variant caused excessive exon 2 skipping due to alternative splicing in these patients, suggesting that this abberant splicing was causal of thier phenotype. Transfection of wild-type and  G304R variant MEFV constructs into HEK293T cells resulted in aberrant splicing of the mutant construct leading to abnormal protein size, presumably causing loss of pyrin function (Tone_2012_ PMID: 21562927). This p.G304R was also identified in dbSNP (ID: rs75977701), ClinVar (classified as benign by Invitae, likely benign by Counsyl, likely pathogenic by GeneDx and as a VUS by ARUP Laboratories and Integrated Genetics), Cosmic (FATHMM prediction of neutral; score=0.00) and LOVD 3.0. The variant was identified in control databases in 1318 of 281346 chromosomes (12 homozygous) at a frequency of 0.004685 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: European (Finnish) in 686 of 25046 chromosomes (freq: 0.02739), East Asian in 360 of 19930 chromosomes (freq: 0.01806), Other in 46 of 7206 chromosomes (freq: 0.006384), Ashkenazi Jewish in 43 of 10360 chromosomes (freq: 0.004151), South Asian in 33 of 30606 chromosomes (freq: 0.001078), European (non-Finnish) in 130 of 127858 chromosomes (freq: 0.001017) and African in 20 of 24910 chromosomes (freq: 0.000803); it was not observed in the Latino population. The p.Gly304Arg variant occurs in the last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. Further,  4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the loss of the 5' splice site. The functional study by Tone et al. described above also confirmed this abberant splicing prediction (Tone_2012_ PMID: 21562927). However, the p.Gly304 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000414140	SCV001928298	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000508393	SCV001965771	benign	not specified		no assertion criteria provided	clinical testing