Submissions for variant NM_000138.5(FBN1):c.6820T>C (p.Cys2274Arg)

dbSNP: rs869025412

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000208376	SCV005387627	likely pathogenic	Marfan syndrome	2024-08-22	reviewed by expert panel	curation	NM_00138 c.6820T>C is a missense variant in FBN1 predicted to cause a substitution of cysteine by arginine at amino acid 2274 (p.Cys2274Arg). This variant is not reported in the literature. This variant has been reported twice in ClinVar as Likely pathogenic and once as uncertain significance (Variation ID: 222610). This variant is not present in gnomAD (PM2_Sup; https://gnomad.broadinstitute.org/ v4.0.0). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.992, PP3). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PM2_Sup,PP2, PP3
Blueprint Genetics	RCV000208376	SCV000263907	likely pathogenic	Marfan syndrome	2015-02-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515543	SCV003349391	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-05-06	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Cys2274 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 17657824), 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 222610). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2274 of the FBN1 protein (p.Cys2274Arg).
Revvity Omics, Revvity	RCV003144160	SCV003834006	uncertain significance	not provided	2021-07-07	criteria provided, single submitter	clinical testing