ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2624G>A (p.Cys875Tyr) (rs886039038)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000251722 SCV000319764 likely pathogenic Cardiovascular phenotype 2015-05-27 criteria provided, single submitter clinical testing Other data supporting pathogenic classification;Rarity in general population databases (dbSNP, ESP, 1000 Genomes);in silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769646 SCV000901047 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-09-01 criteria provided, single submitter clinical testing
Invitae RCV001063194 SCV001228030 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 875 of the FBN1 protein (p.Cys875Tyr). 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 FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 264089). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Cys875 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843, 28973303), which suggests that this may be a clinically significant amino acid residue. 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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