ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.586G>T (p.Gly196Trp) (rs104895179)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000175563 SCV000227071 benign not specified 2015-04-03 criteria provided, single submitter clinical testing
GeneDx RCV000587560 SCV000279039 uncertain significance not provided 2018-02-20 criteria provided, single submitter clinical testing The G196W variant has been published previously in association with systemic juvenile idopathic arthritis, early onset renal amyloidosis, and as a complex allele in a patient with FMF who was also homozygous for the M694V variant in the MEFV gene (Cantarini et al., 2012; Gunesacar et al., 2014). The G196W variant was observed at a frequency of 1%, 38/3960 alleles, in individuals of African American ancestry by the NHLBI Exome Sequencing Project. The 1000 Genomes Database reports that the G196W variant was observed in 1.9%, 25/1322 alleles in individuals of African ancestry, including 3.7%, 8/216 alleles in individuals of Yoruba ancestry (McVean et al., 2012). G196W is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (G197R) has been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000175563 SCV000604183 uncertain significance not specified 2016-12-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587560 SCV000696076 uncertain significance not provided 2016-07-20 criteria provided, single submitter clinical testing Variant Summary: The MEFV variant, c.586G>T (p.Gly196Trp), causes a missense change involving a non-conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured here due to low reliability index value) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.20%, predominantly observed in the African subpopulation at a frequency of 2.4%. This frequency slightly exceeds the maximal expected allele frequency for a pathogenic variant in MEFV (2.2%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. The variant has been reported in the literature in at least 2 FMF patients, one of whom also had a common pathogenic mutation in the homozygous state (c.2082G>A, M694I; Gunesacar_2014), suggesting the variant of interest was not the causitive mutation in this individual. The variant has also been reported in atypical FMF patients and a Systemic Juvenile Idiopathic Arthritis patient, however the variant was the only detected variant in these patients. In addition, one reputable clinical lab has classified the variant as "benign", without evidence to independently evaluate. Taken together, this variant has been classified as a variant of uncertain significance, possibly benign variant, until additional information becomes available.
Invitae RCV000083784 SCV000753991 benign Familial Mediterranean fever 2019-12-31 criteria provided, single submitter clinical testing
Mendelics RCV000083784 SCV001139883 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083784 SCV000115882 not provided Familial Mediterranean fever no assertion provided not provided

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