Submissions for variant NM_000138.5(FBN1):c.6541T>C (p.Cys2181Arg)

dbSNP: rs1131691373

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494127	SCV000581992	likely pathogenic	not provided	2015-08-04	criteria provided, single submitter	clinical testing	The C2181R variant has not been published as a pathogenic variant or been reported as a benign polymorphism to our knowledge. The C2181R 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 C2181R 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. Additionally, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant in this same residue (C2181F) and missense variant in nearby residues (G2173S, I2185T) have been reported in the Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Moreover, this variant affects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud G et al., 2003).Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000722112	SCV000695584	uncertain significance	not specified	2018-05-15	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.6541T>C (p.Cys2181Arg) results in a non-conservative amino acid change located in one of the EGF-like calcium-binding domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245966 control chromosomes (gnomAD). 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.6541T>C in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, the variant causes the substitution of a cysteine residue, which is a common mechanism of FBN1 dysfunction. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until additional information becomes available.