Submissions for variant NM_000138.5(FBN1):c.1633C>T (p.Arg545Cys)

dbSNP: rs730880099

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000157225	SCV000206949	pathogenic	Marfan syndrome	2015-11-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000256026	SCV000321630	pathogenic	not provided	2021-11-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID#180352; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 11700157, 20021881, 20564469, 12446365, 27611364, 22772377, 28642162, 25053872, 31447099, 32123317, 12938084, 19159394, 27353645, 9338581, 17679947)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507510	SCV000603631	pathogenic	not specified	2017-03-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589881	SCV000695462	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2016-10-10	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.1633C>T (p.Arg545Cys) variant involves the alteration of a highly conserved nucleotide and is located in the Ca2+-binding EGF-like #4 domain with 5/5 in silico tools predicting a deleterious outcome. This change disrupts disulfide bonds 541-555 (C4) which affects the secondary or tertiary structure and possibly impairing fibrillin interactions. The variant is absent from control dataset of ExAC and but has been reported in numerous affected individuals predominantly with isolated EL via published reports, although several pts with classical MFS have also been reported, including within families presenting with EL. Two published reports clearly indicate segregation of the variant with the disease (Hayward, 1997 and Li, 2016). The variant has been cited by several reputable databases/clinical laboratories as Pathogenic. Taking together, the variant was classified as Pathogenic.
Ambry Genetics	RCV002313006	SCV000738771	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-12-07	criteria provided, single submitter	clinical testing	The p.R545C pathogenic mutation (also known as c.1633C>T), located in coding exon 13 of the FBN1 gene, results from a C to T substitution at nucleotide position 1633. The arginine at codon 545 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #04 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31): 32924-32931). This alteration has been described in several patients with ectopia lentis and Marfan syndrome (Loeys B et al. Arch Intern Med. 2001;161(20):2447-54; Jin C et al. Mol Vis. 2007;13:1280-4, Comeglio P et al. Hum Mutat. 2007;28(9):928). Additionally, this alteration was observed to co-segregate in multiple relatives in two unrelated multi-generation families (Hayward C et al. Hum Mutat. 1997;10(4):280-9; Li Y et al. Clin. Chim. Acta, 2016 Sep;460:102-6). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, p.R545C is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631935	SCV000753038	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2025-01-27	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 545 of the FBN1 protein (p.Arg545Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ectopia lentis and/or Marfan syndrome (PMID: 9338581, 12446365, 15241795, 17679947, 19159394, 20564469, 27353645, 27611364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180352). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763358	SCV000894048	pathogenic	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2022-04-11	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000157225	SCV001434916	pathogenic	Marfan syndrome	2018-10-13	criteria provided, single submitter	clinical testing	The c.1633C>T (p.Arg545Cys) variant in the FBN1 gene has been reported in multiple patients and segregated in two unrelated families with Marfan syndrome (PMID: 9338581, 11700157, 17657824, 19159394, 25944730, 27353645). The variant is not observed in the gnomAD. Therefore, this c.1633C>T (p.Arg545Cys) variant is classified as pathogenic.
Suma Genomics	RCV003105802	SCV003762219	pathogenic	Ectopia lentis 1, isolated, autosomal dominant		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV002313006	SCV003837683	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-11-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002313006	SCV004357464	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 545 in an epidermal-growth-factor (EGF)-like domain of the FBN1 protein. Although functional studies have not been reported, this variant generates a cysteine residue in an important functional domain and is likely to affect protein structure and stability (PMID: 4750422, 16677079). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in multiple individuals affected with Marfan syndrome, ectopia lentis or aortopathy (PMID: 12446365, 15241795, 17679947, 19159394, 20564469, 27611364, 27353645). This variant has been reported to segregate with aortic dissection and ectopia lentis in ten individuals from a family affected with Marfan syndrome (PMID: 27353645). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003105802	SCV005398938	pathogenic	Ectopia lentis 1, isolated, autosomal dominant	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have rarely been reported (PMID: 27274304; 31950671). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calcium binding EGF domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in Clinvar, and has been observed in individuals with ectopia lentis or Marfan syndrome in the literature (PMIDs: 12446365, 25053872). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000256026	SCV005414278	pathogenic	not provided	2024-09-10	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM1, PM2, PS4_moderate
Molecular Genetics, Royal Melbourne Hospital	RCV000157225	SCV005900363	pathogenic	Marfan syndrome	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change in FBN1 is predicted to replace arginine with cysteine at codon 545, p.(Arg545Cys). The arginine residue is highly conserved (100 vertebrates, Multiz Alignments), and introduces an odd number of cysteine residues in EGF-like calcium binding domain 8 expected to disrupt the disulphide bonds in this domain enhancing proteolytic susceptibility (PMID: 15161917). There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.0004% (5/1,179,436 alleles) in the European (non-Finnish) population. This variant has been reported in multiple unrelated probands with a clinical diagnosis of Marfan Syndrome and segregates with disease in multiple families (PMID: 34281902, 25053872, 25652356, 31741853, 12446365). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.907) and predicts no impact on splicing (SpliceAI) for the nucleotide change. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4, PM1, PM2_Supporting, PP3.
Center for Medical Genetics Ghent, University of Ghent	RCV000157225	SCV000786772	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing