Submissions for variant NM_000243.3(MEFV):c.866C>T (p.Ala289Val)

gnomAD frequency: 0.00006  dbSNP: rs104895132

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594000	SCV000702665	uncertain significance	not provided	2016-11-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000083802	SCV001139867	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000083802	SCV001418589	uncertain significance	Familial Mediterranean fever	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 289 of the MEFV protein (p.Ala289Val). This variant is present in population databases (rs104895132, gnomAD 0.02%). This missense change has been observed in individual(s) with MEFV-related conditions (PMID: 20041150, 25821352). ClinVar contains an entry for this variant (Variation ID: 97550). 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.
GeneDx	RCV000594000	SCV002005213	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17665448, 26984802, 19790133, no PMID, 20041150, 25821352, 34426522, 35358658, 31512232)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262656	SCV002542310	uncertain significance	Autoinflammatory syndrome	2021-04-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483165	SCV002781247	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2022-04-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114248	SCV003800685	uncertain significance	not specified	2023-01-04	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.866C>T (p.Ala289Val) results in a non-conservative amino acid change in 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 0.00012 in 251310 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00012 vs 0.022), allowing no conclusion about variant significance. c.866C>T has been reported in the literature in individuals affected with Familial Mediterranean Fever, Periodic Syndrome and Stills disease who carried the variant in the heterozygous state, with no second allele reported (Feng_2009, Perko_2015, Sighart_2018, Rostmaizadeh_2019). Additionally, the variant was reported as a de novo mutation in a heterozygous patient with recurrent attacks of fever, abdominal pain, vomiting, constipation and oral aphthosis (Kosukcu_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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.
Genome-Nilou Lab	RCV000083802	SCV003802247	likely benign	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126493	SCV003802248	benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126494	SCV003802249	benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083802	SCV000115901	not provided	Familial Mediterranean fever		no assertion provided	not provided
Natera, Inc.	RCV000083802	SCV002087428	uncertain significance	Familial Mediterranean fever	2020-03-30	no assertion criteria provided	clinical testing