ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7402T>C (p.Cys2468Arg) (rs1085308004)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620839 SCV000738762 uncertain significance Cardiovascular phenotype 2016-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000489574 SCV000577818 likely pathogenic not provided 2017-08-22 criteria provided, single submitter clinical testing The C2468R variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The C2468R variant 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. The C2468R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues [K2460R, N2461T, C2470Y, C2470W, Y2474C] have been reported in the Human Gene Mutation Database in association with Marfan syndrome and aortic aneurysm (Stenson et al., 2014), supporting the functional importance of this region of the protein. This variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Petrovsky Russian Research Center of Surgery, The Federal Agency for Scientific Organizations RCV000791340 SCV000930623 likely pathogenic Marfan syndrome 2019-08-01 criteria provided, single submitter clinical testing The p.C2468R variant was previously reported in the ClinVar (Variation ID:427179) but is absent from large population study. Evaluation was done with in silico method with the use of NetGene2, PolyPhen2, Provean and SIFT. Provean and SIFT show a deleterious effect, whereas PolyPhen2 only results in possibly damaging. To help further invistigate significance, revised Ghent nosology of Marfan syndrome (doi:10.1136/jmg.2009.072785) has criterias suggesting any Cysteine substitution in Fibrillin-1 has a damaging effect. Additionally, FBN1 gene is known to be more intolerant to missense variants: ExAC Z score = 5.33 - meaning less benign results with missense variants. Our conclusion: it is a likely pathogenic variant. Functional study deemed necessary for guaranteed pathogenic evaluation.

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