Submissions for variant NM_000138.5(FBN1):c.4405C>T (p.Arg1469Cys)

gnomAD frequency: 0.00003  dbSNP: rs587782946

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000143893	SCV004218519	uncertain significance	Marfan syndrome	2023-12-29	reviewed by expert panel	curation	NM_000138.5 c.4405C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 1469 (p.Arg1469Cys). This variant has been identified in at least two individuals in the literature including one proband with thoracic aortic aneurysm and dissection (TAAD) and one without specific phenotype details available (PS4_supporting; PMIDs: 33824467, 27906200). This variant is present in gnomAD, with a maximum frequency of 0.0066% (1/15268 alleles) in the Admixed American subpopulation (https://gnomad.broadinstitute.org/, v3.1.2); please note that despite this frequency exceeding the threshold for application of BS1 per the VCEP specifications, because of the small total allele count for this subpopulation, the VCEP opted not to apply any population criteria based on this evidence. This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.772). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). However, due to insufficient evidence, this variant is classified as of uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_supporting, PP2, PP3.
Color Diagnostics, LLC DBA Color Health	RCV001189649	SCV001356980	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1469 in a calcium-binding EGF-like domain of the FBN1 protein. Cysteine creating variants in cbEGF-like domains have been shown to affect protein stability and are overrepresented among patients with Marfan syndrome (PMID: 15161917, 16571647, 17701892). 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 performed for this variant. This variant has been reported in an individual affected with isolated thoracic aortic aneurysm and aortic dissection (PMID: 33824467). This variant has been identified in 3/282638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different amino acid change at the same position (p.Arg1469Pro) has been observed in a family affected with Marfan syndrome (Clinvar variation ID: 42361). Additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374755	SCV001439536	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Invitae	RCV001857489	SCV002185633	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-04-23	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg1469 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 29543232), which suggests that this may be a clinically significant amino acid residue. 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: 155793). This missense change has been observed in individual(s) with FBN1-related conditions (PMID: 27906200, 33824467). This variant is present in population databases (rs587782946, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1469 of the FBN1 protein (p.Arg1469Cys).
All of Us Research Program, National Institutes of Health	RCV000143893	SCV004814730	uncertain significance	Marfan syndrome	2023-05-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1469 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/282638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different amino acid change at the same position (p.Arg1469Pro) has been observed in a family affected with Marfan syndrome (Clinvar variation ID: 42361). Additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV004589636	SCV005079141	likely pathogenic	not provided	2023-12-09	criteria provided, single submitter	clinical testing	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 (PMID: 12938084); 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; This variant is associated with the following publications: (PMID: 27906200, 33824467, 12938084)
Blueprint Genetics	RCV000143893	SCV000188762	likely pathogenic	Marfan syndrome	2013-12-20	no assertion criteria provided	clinical testing