Description
This sequence change replaces cysteine with serine at codon 1389 of the FBN1 protein (p.Cys1389Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant disrupts the p.Cys1389 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 14695540, 28550590), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Marfan syndrome (PMID: 28973303, Invitae). ClinVar contains an entry for this variant (Variation ID: 406277). This variant is not present in population databases (ExAC no frequency).
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |