Submissions for variant NM_000243.3(MEFV):c.1341G>C (p.Lys447Asn)

gnomAD frequency: 0.00011  dbSNP: rs756322372

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000398473	SCV000329421	uncertain significance	not provided	2022-12-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28421071, 30019023)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044845	SCV001208665	uncertain significance	Familial Mediterranean fever	2022-07-27	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 447 of the MEFV protein (p.Lys447Asn). This variant is present in population databases (rs756322372, 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: 279849). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine 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.
Illumina Laboratory Services, Illumina	RCV001044845	SCV001277727	uncertain significance	Familial Mediterranean fever	2017-05-24	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264418	SCV001442549	uncertain significance	not specified	2020-10-17	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.1341G>C (p.Lys447Asn) 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-05 in 251490 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (5.6e-05 vs 0.022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1341G>C in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000398473	SCV001500047	uncertain significance	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002487174	SCV002777410	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2022-01-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001044845	SCV003802157	likely benign	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126659	SCV003802158	benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126660	SCV003802159	benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000398473	SCV004227513	uncertain significance	not provided	2022-05-12	criteria provided, single submitter	clinical testing	BP4
Natera, Inc.	RCV001044845	SCV001458302	uncertain significance	Familial Mediterranean fever	2019-10-28	no assertion criteria provided	clinical testing