Description
Variant summary: FBN1 c.4727T>C (p.Met1576Thr) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 252050 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4727T>C has been reported in the literature in at least one individual with an unknown bicuspid aortic valve phenotype (e.g. Gillis_2017). The variant has also been reported in the literature in individuals with Adolescent Idiopathic Scoliosis and suspected Marfan Syndrome (e.g. Rommel_2005, Rybczynski_2008, Sheikhzadeh_2012, Buchan_2014, Madar_2019, Damrauer_2019). Several of the individuals described in these reports underwent clinical genetics evaluations and had a normal range of Ghent systemic features (4 to 5 points, e.g. Buchan_2014, Madar_2019) or were reported without cardiac involvement (e.g. Damrauer_2019). The patients described by Buchan et al. were reported to have normal echocardiograms and ophthalmological evaluations, and no family history of aortic aneurysm or scoliosis, therefore suggesting possible lack of co-segregation with disease. These reports do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24833718, 31211626, 28659821, 26333736, 31163209, 16220557, 19012347, 21883168). Eight ClinVar submitters (evaluation after 2014) have cited the variant; seven submitters classified the variant as uncertain significance, and one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
