Submissions for variant NM_000243.3(MEFV):c.1886dup (p.Pro630fs)

gnomAD frequency: 0.00003  dbSNP: rs876660997

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223444	SCV000279054	likely pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 152 amino acids are replaced with 1 different amino acid, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19302049)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801477	SCV000941254	uncertain significance	Familial Mediterranean fever	2022-07-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro630Alafs*2) in the MEFV gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 152 amino acid(s) of the MEFV protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 234364). 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.
Fulgent Genetics, Fulgent Genetics	RCV002485439	SCV002791025	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2022-02-24	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000801477	SCV003802020	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126629	SCV003802021	uncertain significance	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126630	SCV003802022	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226258	SCV003922577	uncertain significance	not specified	2023-03-18	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.1886dupT (p.Pro630AlafsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein due to its location in the last exon region where nonsense-mediated decay is not expected. At-least one truncation downstream of this position, namely c.2330dupG (p.Gln778Serfs*4) has been reported in association with features of mild Familial Mediterranean Fever (FMF) in an individual who was reportedly compound heterozygous with the well known pathogenic MEFV variant p.Met694Val (example, Duncan_2014). The variant allele was found at a frequency of 4.1e-06 in 241462 control chromosomes. To our knowledge, no occurrence of c.1886dupT in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.