Submissions for variant NM_000138.5(FBN1):c.6815A>G (p.Tyr2272Cys)

dbSNP: rs2141232534

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001909401	SCV002187276	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-09-06	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. 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: 1407992). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 17627385, 17657824, 21895641; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2272 of the FBN1 protein (p.Tyr2272Cys).
GeneDx	RCV003228020	SCV003924918	likely pathogenic	not provided	2022-11-14	criteria provided, single submitter	clinical testing	Reported in a patient with ectopia lentis and minor skeletal and skin features (Comeglio et al., 2007; Aragon-Martin et al., 2010) and in a patient with mitral valve prolapse and dilated aortic root (Duan et al., 2021) in published literature; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Introduces a new cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 20564469, 32123317, 17657824, 34628919, 21895641, 17627385, 12938084)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003485744	SCV004240587	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-04-04	criteria provided, single submitter	clinical testing