Submissions for variant NM_000138.5(FBN1):c.6724C>T (p.Arg2242Cys)

gnomAD frequency: 0.00001  dbSNP: rs779749926

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422604	SCV000525111	likely pathogenic	not provided	2022-12-13	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 (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27527004, 31589614, 25944730, 12938084)
Color Diagnostics, LLC DBA Color Health	RCV001183817	SCV001349650	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2242 in an EGF-like calcium-binding domain 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). 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 25944730), in over ten individuals who were not affected Marfan syndrome (doi: 10.21203/rs.3.rs-2085746/v1, ClinVar SCV002577457.1), and in a few individuals enrolled in population-based studies who were unknown to have Marfan syndrome or related features (PMID: 32989268, 34428338). This variant has been identified in 3/250968 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000422604	SCV002501244	uncertain significance	not provided	2022-01-28	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002286733	SCV002577457	likely benign	Marfan syndrome	2021-12-21	criteria provided, single submitter	clinical testing	BS2, PM2, PP3
Invitae	RCV002525380	SCV003009313	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2242 of the FBN1 protein (p.Arg2242Cys). This variant is present in population databases (rs779749926, gnomAD 0.003%). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 25944730). ClinVar contains an entry for this variant (Variation ID: 384344). 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 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.
Ambry Genetics	RCV001183817	SCV003635525	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-08	criteria provided, single submitter	clinical testing	The c.6724C>T (p.R2242C) alteration is located in exon 55 (coding exon 54) of the FBN1 gene. This alteration results from a C to T substitution at nucleotide position 6724, causing the arginine (R) at amino acid position 2242 to be replaced by a cysteine (C). This alteration has been reported in an individual with Marfan syndrome (Wooderchak-Donahue, 2015). This amino acid position is well conserved in available vertebrate species. The p.R2242C amino acid is located in the cbEGF34 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cystine residues within cbEGF domains (Vollbrandt, 2004). This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV002286733	SCV004822433	uncertain significance	Marfan syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2242 in an EGF-like calcium-binding domain 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). 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 25944730), in over ten individuals who were not affected Marfan syndrome (doi: 10.21203/rs.3.rs-2085746/v1, ClinVar SCV002577457.1), and in a few individuals enrolled in population-based studies who were unknown to have Marfan syndrome or related features (PMID: 32989268, 34428338). This variant has been identified in 3/250968 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.