ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.3719G>A (p.Cys1240Tyr) (rs1554122896)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617471 SCV000738998 likely pathogenic Cardiovascular phenotype 2017-01-11 criteria provided, single submitter clinical testing The p.C1240Y variant (also known as c.3719G>A), located in coding exon 28 of the FBN2 gene, results from a G to A substitution at nucleotide position 3719. The cysteine at codon 1240 is replaced by tyrosine, an amino acid with highly dissimilar properties. In one study, 13 of 14 reported FBN2 mutations were found in the middle region of the gene (exons 24-36), and 7 of these mutations were noted to alter or produce a cysteine residue (Callewaert BL et al. Hum Mutat. 2009;30(3):334-341). Based on internal structural analysis, p.C1240Y is predicted to eliminate a conserved disulfide in the cb EGF-like domain #15, suggesting disruption of folding of this domain (Downing AK et al. Cell. 1996;85:597-605). In one study, this variant was reported in a child with Beals syndrome (also known as congenital contractural arachnodactyly (CCA)), and the authors described the occurrence to be de novo (Semyachkina AN et al. Russian Bulletin of Perinatology and Pediatrics. 2016;61(5):47-51 [In Russian]). Another alteration involving the same amino acid, p.C1240R (referred to as p.C1239R), also has been reported in a patient with CCA (Gupta PA et al. Hum Mutat. 2002;19:39-48). This amino acid position is highly conserved in available vertebrate species. In addition, p.C1240Y is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001220794 SCV001392805 uncertain significance Congenital contractural arachnodactyly 2019-05-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1240 of the FBN2 protein (p.Cys1240Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FBN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 519834). This variant affects a cysteine residue located within an epidermal growth factor (EGF)–like domain of the FBN2 protein. Cysteine residues in these domains are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN2 EGF-like domains affecting cysteine residues are overrepresented in patients with congenital contractural arachnodactyly (PMID: 18767143). 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.

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