Submissions for variant NM_000243.3(MEFV):c.2150G>T (p.Arg717Leu)

dbSNP: rs545517350

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000989472	SCV001139814	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002516	SCV001160475	uncertain significance	not specified	2019-04-15	criteria provided, single submitter	clinical testing	The MEFV c.2150G>T; p.Arg717Leu variant (rs545517350) is reported in the medical literature in one individual with a reported periodic fever syndrome (Gattorno 2009). Another variant in the same codon, p.Arg717His, has also been described in an individual with a periodic fever syndrome (Vergara 2012). However, an expert panel has classified the c.2150G>T; p.Arg717Leu variant as a variant of uncertain significance (Van Gijn 2018). The variant is reported in the general population with an allele frequency of 0.003% (7/251492 alleles) in the Genome Aggregation Database. The arginine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Due to limited information, the clinical significance of the variant is uncertain at this time. References: Gattorno M et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009 Oct;124(4):e721-8. Van Gijn ME et al. New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID). J Med Genet. 2018 Aug;55(8):530-537. Vergara C et al. Clinical and genetic features of hereditary periodic fever syndromes in Hispanic patients: the Chilean experience. Clin Rheumatol. 2012 31(5):829-34.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001002516	SCV002041513	uncertain significance	not specified	2021-11-30	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.2150G>T (p.Arg717Leu) results in a non-conservative amino acid change located in the SPRY domain (IPR003877) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. A recent report utilizing the meta predictor tool, REVEL (Rare Exome Variant Ensemble Learner) to assess the pathogenicity of MEFV variants with ambiguous classification proposed a likely pathogenic outcome for this variant (Accetturo_2019). In this study, REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Auto Inflammatory Diseases. The variant allele was found at a frequency of 2.8e-05 in 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2150G>T has been reported in the literature in heterozygous state in an Italian individual affected with Familial Mediterranean Fever (Gattorno_2009, Federici_2012). These reports do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. Another variant affecting the same amino acid residue (R717H) has been reported in an effected individual (PMID 22281876). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The variant, Arg717Leu, has been reported by the International Study Group for Systemic Autoinflammatory Diseases (INSAID), with an experts' consensus as "VUS" (Van Gijn_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002479155	SCV002775310	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2024-01-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000989472	SCV003802622	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003127563	SCV003802633	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003127564	SCV003802645	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000989472	SCV002093882	uncertain significance	Familial Mediterranean fever	2020-03-03	no assertion criteria provided	clinical testing