ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2926C>T (p.Arg976Cys) (rs548296552)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181470 SCV000233772 pathogenic not provided 2014-05-12 criteria provided, single submitter clinical testing p.Arg976Cys (CGC>TGC): c.2926 C>T in exon 25 of the FBN1 gene (NM_000138.4)While the R976C mutation in the FBN1 gene has not been reported to our knowledge, a mutation affecting this same residue, R976H, has been reported in a 22 year-old patient with classic Marfan syndrome (Comeglio et al., 2007). Additionally, mutations in nearby residues (R974C, C980S) have been reported in association with Marfan syndrome, further supporting the functional importance of this residue and this region of the protein. R976C results in a non-conservative amino acid substitution at a position that is conserved across species. In silico analysis predicts this change is damaging to the protein structure/function. The R976C mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, R976C in the FBN1 gene is interpreted as a likely disease-causing mutation. The variant is found in TAAD panel(s).
Invitae RCV001057247 SCV001221730 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 976 of the FBN1 protein (p.Arg976Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs548296552, ExAC 0.001%). This variant has not been reported in the literature in individuals with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 200006). 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: Probably Damaging; Align-GVGD: Class C0). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192951 SCV001361430 uncertain significance not specified 2019-03-04 criteria provided, single submitter clinical testing Variant summary: FBN1 c.2926C>T (p.Arg976Cys) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277204 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2926C>T in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Missense affecting or creating cysteine residues are listed as one of the criteria for causal FBN1 mutations in the revised Ghent criteria for the diagnosis of Marfan syndrome (MFS) and related conditions (Loeys BL et al., J Med Genet 2010; 47:476-485). Based on the evidence outlined above, unless additional clinical and functional evidence are obtained, the variant was classified as VUS-possibly pathogenic.
Department of Vascular Biology,Beijing Anzhen Hospital RCV001374768 SCV001439549 uncertain significance Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research

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