Submissions for variant NM_000243.3(MEFV):c.623G>C (p.Ser208Thr)

dbSNP: rs759326778

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001247261	SCV001420670	uncertain significance	Familial Mediterranean fever	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine with threonine at codon 208 of the MEFV protein (p.Ser208Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs759326778, ExAC 0.01%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 30355575). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 971473). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MEFV function (PMID: 30355575). 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 Diagnostics Laboratory, The Hospital for Sick Children	RCV002264251	SCV002542296	uncertain significance	Autoinflammatory syndrome	2018-05-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001247261	SCV003802290	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003127733	SCV003802291	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003127734	SCV003802292	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	RCV003235515	SCV003934373	uncertain significance	not specified	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.623G>C (p.Ser208Thr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 238594 control chromosomes (gnomAD). c.623G>C has been reported in the literature in two homozygous siblings affected with familial autoinflamation (Hong_2019). The unaffected sibling and parents were heterozygous with the variant, showing some evidence of cosegregation with disease. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on cell death, finding a significant increase in spontaneous cell death in macrophages transfected with the variant construct (Honda_2021). The following publications have been ascertained in the context of this evaluation (PMID: 26215181, 30355575, 33733382). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.