Submissions for variant NM_000243.3(MEFV):c.1406T>C (p.Val469Ala)

gnomAD frequency: 0.00005  dbSNP: rs778686119

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000336657	SCV000396770	uncertain significance	Familial Mediterranean fever	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468940	SCV000696047	uncertain significance	not specified	2022-11-05	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.1406T>C (p.Val469Ala) 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 4e-05 in 251492 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (4e-05 vs 0.022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1406T>C in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. However, at-least one publications reports its occurrence as a heterozyous VUS in a patient with pharyngitis and adenitis (PFAPA) syndrome (Westwell-Roper_2019). Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263010	SCV002543703	uncertain significance	Autoinflammatory syndrome	2019-12-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002487408	SCV002781329	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2022-05-31	criteria provided, single submitter	clinical testing
Invitae	RCV000336657	SCV003522574	uncertain significance	Familial Mediterranean fever	2022-06-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 469 of the MEFV protein (p.Val469Ala). This variant is present in population databases (rs778686119, 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: 319113). 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.
Genome-Nilou Lab	RCV000336657	SCV003802133	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126670	SCV003802135	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126671	SCV003802136	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000336657	SCV001452076	uncertain significance	Familial Mediterranean fever	2020-09-16	no assertion criteria provided	clinical testing