Submissions for variant NM_000243.3(MEFV):c.2146A>G (p.Lys716Glu)

gnomAD frequency: 0.00002  dbSNP: rs746092199

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000218313	SCV000279061	uncertain significance	not provided	2014-03-24	criteria provided, single submitter	clinical testing	The K716E variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The K716E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K716E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. However, a missense mutation at this residue (K716M) has been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2009), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795673	SCV000935143	uncertain significance	Familial Mediterranean fever	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 716 of the MEFV protein (p.Lys716Glu). This variant is present in population databases (rs746092199, gnomAD 0.01%). 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: 234366). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328382	SCV001519503	uncertain significance	not specified	2024-04-18	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.2146A>G (p.Lys716Glu) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251490 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.2146A>G in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28421071). ClinVar contains an entry for this variant (Variation ID: 234366). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000795673	SCV003802656	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126631	SCV003802667	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126632	SCV003802678	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000795673	SCV002093883	uncertain significance	Familial Mediterranean fever	2019-10-28	no assertion criteria provided	clinical testing