Submissions for variant NM_000243.3(MEFV):c.2123G>A (p.Arg708His)

gnomAD frequency: 0.00003  dbSNP: rs200375017

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804253	SCV000944153	uncertain significance	Familial Mediterranean fever	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 708 of the MEFV protein (p.Arg708His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MEFV-related conditions. ClinVar contains an entry for this variant (Variation ID: 649340). 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 histidine 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.
Fulgent Genetics, Fulgent Genetics	RCV002487716	SCV002788538	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-12-29	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000804253	SCV003801460	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001274311	SCV003801471	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003127470	SCV003801482	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479222	SCV004223262	uncertain significance	not specified	2023-11-30	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.2123G>A (p.Arg708His) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) 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 1.6e-05 in 251486 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.2123G>A in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001274311	SCV001458294	uncertain significance	Familial Mediterranean fever, autosomal dominant	2020-06-10	no assertion criteria provided	clinical testing