ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7865G>C (p.Cys2622Ser)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001047651 SCV001211621 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-06-02 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 2622 of the FBN1 protein (p.Cys2622Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with FBN1-related conditions (PMID: 15241795, Invitae). 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 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). This variant disrupts the p.Cys2622 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 25656438), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286841 SCV001473460 likely pathogenic none provided 2020-04-04 criteria provided, single submitter clinical testing The FBN1 c.7865G>C; p.Cys2622Ser variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 2622 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon, including a variant resulting in the same amino acid change (c.7864T>A; p.Cys2622Ser, c.7864T>C; p.Cys2622Arg) have been reported in individuals with Marfan syndrome (Haine 2015, Loeys 2015). Based on available information, this variant is considered to be likely pathogenic. References: Haine E et al. Muscle and Bone Impairment in Children With Marfan Syndrome: Correlation With Age and FBN1 Genotype. J Bone Miner Res. 2015 Aug;30(8):1369-76. Loeys et al. Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum Mutat. 2004 Aug;24(2):140-6.

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