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
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.
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
Petrovsky Russian Research Center of Surgery, The Federal Agency for Scientific Organizations RCV000791340 SCV000930623 pathogenic Marfan syndrome 2019-08-30 criteria provided, single submitter clinical testing The p.C2468R variant was found in one individual with MFS and is absent from large population studies (ExAC no frequency). ClinVar has an entry for this variant (Variation ID:427179). There is a known different missense variant at same codon C2468Y (UMD-FBN1 ID: 2517). Cysteine is located cbEGF-like domain and participates Disulfide bonds 2455-2468. Cysteine substitutions in EGF domains are common pathogenic mechanisms of the disease (PMID: 1301946, 15161917, 20591885). In Addition, prediction tools like Provean, SIFT, PolyPhen2, MutationTaster show deleterious effect of the variant. Based on this evidences we classify C2468R variant as Pathogenic.

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