ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.338C>G (p.Ser113Cys) (rs869025403)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208445 SCV000263896 likely pathogenic Marfan syndrome 2015-05-18 criteria provided, single submitter clinical testing
Invitae RCV000534760 SCV000627893 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-01-10 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 113 of the FBN1 protein (p.Ser113Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 222600). This variant has been observed in an individual with clinical findings that are highly specific for Marfan syndrome (Invitae). This variant generates a cysteine residue in a two-codon linker region between two epidermal-growth-factor (EGF)–like domains of the FBN1 protein. Cysteine residues in EGF-like domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 4750422, 16677079). Cysteine generating variants in these domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). However, it is uncertain whether this variant would have the same effect because it does not lie within a defined EGF-like domain. In summary, this variant is a rare missense change with uncertain impact on protein function. In the absence of confirmed functional or genetic evidence, at this time it has been classified as a Variant of Uncertain Significance.

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