Submissions for variant NM_000243.3(MEFV):c.2163C>T (p.Phe721=)

gnomAD frequency: 0.00484  dbSNP: rs11466047

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083427	SCV000629037	benign	Familial Mediterranean fever	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588308	SCV000696062	likely benign	not provided	2016-09-16	criteria provided, single submitter	clinical testing	Variant summary: The MEFV c.2163C>T (p.Phe721Phe) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may create multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 215/121666 control chromosomes (2 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0180665 (188/10406). The frequency in Africans is similar to estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). Although there are no exact prevalence reports of FMF in African populations (unlike in other Mediterranean populations where this disease is common), we can consider the prevalence of FMF in Africans to be relatively lower. Therefore, the observed frequency of this variant which reaches ~2% (1.8% in NHLBI ESP and ExAC and 3.4% in HapMap) across multiple African populations is an indication that this variant is unlikely to have a pathogenic outcome or uncertain significance (maximum expected allele frequency for a pathogenic variant in MEFV is 2.2% when overall prevalence is taken at 1 in 400). Additionally, there are two homozygotes reported in the African cohort from ExAC. If only the observed frequencies in African populations were compared with ethnicity-specific disease prevalence (such as rare prevalence in Africans), the pbGP score would support for a benign outcome. Tchernitchko, 2003 reports one non-African patient with the variant, which authors state is in compound heterozygous form with a pathogenic variant (M694I/F721F); however, they do not specify whether a familial segregation study was performed to assign the phase of the variants. Taken together, this variant is classified as likely benign until additional information is available.
GeneDx	RCV000588308	SCV001937118	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263740	SCV002543434	likely benign	Autoinflammatory syndrome	2021-03-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002431547	SCV002729180	likely benign	Inborn genetic diseases	2022-06-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome-Nilou Lab	RCV001083427	SCV003802522	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126805	SCV003802534	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126806	SCV003802545	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001083427	SCV002093880	benign	Familial Mediterranean fever	2019-12-09	no assertion criteria provided	clinical testing