Submissions for variant NM_000243.3(MEFV):c.1643C>A (p.Thr548Asn)

gnomAD frequency: 0.00001  dbSNP: rs550970304

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781531	SCV000919633	uncertain significance	not specified	2017-12-28	criteria provided, single submitter	clinical testing	Variant summary: The MEFV c.1643C>A (p.Thr548Asn) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/277202 control chromosomes at a frequency of 0.0000072, which does not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae	RCV000792803	SCV000932124	uncertain significance	Familial Mediterranean fever	2022-04-08	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 548 of the MEFV protein (p.Thr548Asn). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 633304). 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 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.
GeneDx	RCV001555989	SCV001777490	uncertain significance	not provided	2020-05-29	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263975	SCV002543716	uncertain significance	Autoinflammatory syndrome	2021-02-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000792803	SCV003802073	likely benign	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126934	SCV003802074	benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126935	SCV003802075	benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000792803	SCV001462105	uncertain significance	Familial Mediterranean fever	2020-09-16	no assertion criteria provided	clinical testing