Submissions for variant NM_000138.5(FBN1):c.2920C>T (p.Arg974Cys)

gnomAD frequency: 0.00001  dbSNP: rs397514558

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548224	SCV000627874	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-15	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 974 of the FBN1 protein (p.Arg974Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with isolated ectopia lentis and Marfan syndrome (PMID: 17627385, 17657824, 22539873). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39667). 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%. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000726909	SCV000704117	pathogenic	not provided	2016-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001186221	SCV000738929	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-04-19	criteria provided, single submitter	clinical testing	The p.R974C pathogenic mutation (also known as c.2920C>T), located in coding exon 24 of the FBN1 gene, results from a C to T substitution at nucleotide position 2920. The arginine at codon 974 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the TGFBP#03 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues (Collod-Béroud G et al. Hum. Mut. 2003:22(3):199-208). This particular mutation has been reported in a number of Marfan syndrome (MFS) and ectopia lentis (EL) cohorts (Comeglio P et al. Hum. Mutat. 2007;28:928; Howarth R et al. Genet. Test. 2007;11:146-52; Stheneur C et al. Eur. J. Hum. Genet. 2009;17:1121-8; Li J et al. Mol. Vis. 2014;20:1017-24; Vatti L et al. Am. J. Med. Genet. A. 2017;173:2995-3002). This variant also segregated with ectopia lentis in one large Chinese family (Yang G et al. Mol. Vis. 2012;18:945-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000032871	SCV000781346	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub	RCV000032871	SCV000845663	likely pathogenic	Marfan syndrome	2017-07-27	criteria provided, single submitter	clinical testing	The FBN1 c.2920C>T variant has previously been reported in 9 affected members of a 5 generation family with isolated ectopia lentis (Yang et al. Mol Vis. 2012;18:945-50) and a single patient with Marfan syndrome with major skeletal, ocular and cardiovascular manifestations (Comeglio et al. Hum Mutat. 2007 ;28(9):928). It has not been detected in approximately 120,000 individuals in control populations (gnomAD database). In silico tools predict the variant will adversely affect protein structure and function and it affects a highly conserved TGFB binding domain. This variant is therefore likely to be pathogenic, but may be associated with a variable phenotype. - Other Disease Reports - This variant has been linked to other diseases: Ectopia lentis (pubmed: 22539873) - Missense Effect Predictions - 87.5% (7/8) of algorithms have predicted that this variant will adversely affect protein function
Color Diagnostics, LLC DBA Color Health	RCV001186221	SCV001352587	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 974 in the TGFbeta-like motif 5 of the FBN1 protein. Cysteine creating variants in TGF-beta binding domains have been shown to affect protein stability and are overrepresented among individuals 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 reported for this variant. This variant has been reported in individuals affected with Marfan syndrome or isolated ectopia lentis (PMID: 17627385, 17657824, 22539873, 25053872, 28941062, 34140103, 34281902, ClinVar SCV000845663.2). This variant has been shown to segregate with isolated ectopia lentis in one of the families (PMID: 22539873). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192805	SCV001361165	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2023-02-06	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2920C>T (p.Arg974Cys) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes. c.2920C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g. Comeglio_2007, Howarth_2007, Li_2014, Vatti_2017, Lopez-Sainz_2021). The variant has also been reported to cosegregate with disease in families with an Ectopia Lentis phenotype without other reported symptoms of Marfan Syndrome (Yang_2012, Chen_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight (other) submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000726909	SCV001474003	pathogenic	not provided	2020-02-25	criteria provided, single submitter	clinical testing	The FBN1 c.2920C>T; p.Arg974Cys variant (rs397514558) is reported in the literature in several individuals affected with Marfan syndrome (Comeglio 2007, Stheneur 2009). This variant is also reported to segregate in all affected members of a large, multigenerational kindred affected with ectopia lentis (Yang 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 974 is moderately conserved, it occurs in one of the TGF-beta binding (TB) domains (Yuan 1997), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. TB domains contain eight conserved cysteine residues and the disulfide bridges formed between these residues are essential for protein folding; loss of one of these cysteines or creation of a new cysteine in this domain may interfere with proper disulfide bridge formation, disrupting protein structure (Yuan 1997). Accordingly, the revised Ghent nosology for Marfan syndrome lists missense variants creating or affecting cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 47(7): 476-85. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Yang G et al. A novel FBN1 mutation in a Chinese family with isolated ectopia lentis. Mol Vis. 2012;18:945-50. Yuan X et al. Solution structure of the transforming growth factor beta-binding protein-like module, a domain associated with matrix fibrils. EMBO J. 1997 Nov 17;16(22):6659-66.
OMIM	RCV000032871	SCV000056641	pathogenic	Marfan syndrome	2012-01-01	no assertion criteria provided	literature only
OMIM	RCV000172857	SCV000223833	pathogenic	Ectopia lentis 1, isolated, autosomal dominant	2012-01-01	no assertion criteria provided	literature only
Center for Medical Genetics Ghent, University of Ghent	RCV000032871	SCV000786902	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing