Submissions for variant NM_000138.5(FBN1):c.6461C>G (p.Pro2154Arg)

gnomAD frequency: 0.00001  dbSNP: rs756219617

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001524957	SCV001734942	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 2154 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with ectopia lentis (PMID: 11700157). This variant has been identified in 2/251046 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001756120	SCV001986083	uncertain significance	not provided	2022-08-19	criteria provided, single submitter	clinical testing	Reported in an adult with ectopia lentis and minor skeletal features (Loeys et al., 2001); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; 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: 15054843, 11933199, 11700157)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861732	SCV002201119	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2154 of the FBN1 protein (p.Pro2154Arg). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of FBN1-related conditions (PMID: 11700157; Invitae). ClinVar contains an entry for this variant (Variation ID: 549345). 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 with a positive predictive value of 95%. This variant disrupts the p.Pro2154 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001756120	SCV004702263	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	FBN1: PM1, PP3
All of Us Research Program, National Institutes of Health	RCV000663871	SCV004822443	uncertain significance	Marfan syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 2154 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with ectopia lentis (PMID: 11700157). This variant has been identified in 2/251046 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Center for Medical Genetics Ghent, University of Ghent	RCV000663871	SCV000787234	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing