Submissions for variant NM_000138.5(FBN1):c.6322C>T (p.Arg2108Cys)

dbSNP: rs1246984265

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069594	SCV001234772	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-14	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 549339). This missense change has been observed in individuals with clinical features of FBN1-related conditions (PMID: 27906200, 34550612; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2108 of the FBN1 protein (p.Arg2108Cys).
GeneDx	RCV001823158	SCV002072774	likely pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing	Reported in an FBN1 database in an individual diagnosed with incomplete Marfan syndrome (Groth et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Introduces a new cysteine residue within a TGF-binding protein domain (aka TB domain or 8-Cysteine domain) and is expected to disrupt disulfide bonding within this domain; missense substitutions that affect cysteine residues within this TGF-binding protein domain have been reported in association with various FBN1-related phenotypes, including Marfan syndrome (HGMD).; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21175431, 15062093, 9362480, 7622614, 27906200)
All of Us Research Program, National Institutes of Health	RCV000663862	SCV004833239	uncertain significance	Marfan syndrome	2023-07-07	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000663862	SCV000787221	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing