Submissions for variant NM_000243.3(MEFV):c.566G>T (p.Gly189Val)

gnomAD frequency: 0.00001  dbSNP: rs923516953

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001225884	SCV001398178	uncertain significance	Familial Mediterranean fever	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with valine at codon 189 of the MEFV protein (p.Gly189Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine. 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. 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 valine 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	RCV002497768	SCV002780597	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2022-02-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001225884	SCV003802309	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003127699	SCV003802310	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003127700	SCV003802313	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	RCV004699215	SCV005202842	uncertain significance	not specified	2024-07-24	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.566G>T (p.Gly189Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-06 in 177474 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.566G>T in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 953572). Based on the evidence outlined above, the variant was classified as uncertain significance.