Submissions for variant NM_000243.3(MEFV):c.2122C>T (p.Arg708Cys)

gnomAD frequency: 0.00002  dbSNP: rs104895202

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780404	SCV000917626	uncertain significance	not specified	2018-12-24	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.2122C>T (p.Arg708Cys) results in a non-conservative amino acid change located in the Butyrophylin-like, SPRY domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246268 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2122C>T in individuals affected with Familial Mediterranean Fever has been reported. One publication reports in silico molecular modeling of this variant, however, does not allow convincing conclusions about the variant effect (Arakelov_2015). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000083748	SCV001407079	uncertain significance	Familial Mediterranean fever	2022-02-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 708 of the MEFV protein (p.Arg708Cys). This variant is present in population databases (rs104895202, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of MEFV-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 97496). 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 cysteine 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262641	SCV002543737	uncertain significance	Autoinflammatory syndrome	2019-05-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000083748	SCV002579694	uncertain significance	Familial Mediterranean fever	2021-11-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000083748	SCV003801494	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126449	SCV003801505	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126450	SCV003801516	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV004791263	SCV005411233	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	BP4, PS4_moderate
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083748	SCV000115842	not provided	Familial Mediterranean fever		no assertion provided	not provided
Natera, Inc.	RCV000083748	SCV001462094	uncertain significance	Familial Mediterranean fever	2020-09-16	no assertion criteria provided	clinical testing