Submissions for variant NM_000138.5(FBN1):c.718C>T (p.Arg240Cys)

dbSNP: rs137854480

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307365	SCV000052427	pathogenic	Familial ectopia lentis	2022-10-03	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.718C>T (p.Arg240Cys) results in a non-conservative amino acid change in 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 251516 control chromosomes (gnomAD). c.718C>T has been reported in the literature in multiple individuals affected with Marfan syndrome, features of Marfan syndrome or isolated ectopia lentis (examples: Loeys_2001, Korkko_2002, Comeglio_2002, Ades_2004 and Aragon-Martin_2010). These data indicate that the variant is very likely to be associated with disease. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000017924	SCV000058916	pathogenic	Marfan syndrome	2008-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000181681	SCV000233984	pathogenic	not provided	2023-06-09	criteria provided, single submitter	clinical testing	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; Introduces a cysteine residue within a TGF-binding protein domain (aka TB domain or 8-Cysteine domain) and is expected to disrupt disulfide bonding within this domain; other missense substitutions that affect cysteine residues within this TGF-binding protein domain have been reported in association with various FBN1-related phenotypes, including Marfan syndrome (HGMD); This variant is associated with the following publications: (PMID: 34818515, 20564469, 9399842, 15054843, 12446365, 11826022, 14695540, 19293843, 17627385, 17679947, 17657824, 30838813, 30675029, 32679894, 33087929, 31950671, 29357934, 17701892, 11700157, 18079676)
Fulgent Genetics, Fulgent Genetics	RCV000515367	SCV000611194	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	2021-10-20	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000017924	SCV000678236	pathogenic	Marfan syndrome	2017-08-01	criteria provided, single submitter	clinical testing	FBN1:NM_000138.4:exon7 p.Arg240Cys (c.718C>T): This variant has been reported in >5 individuals with Marfan syndrome, features of Marfan syndrome or isolated ectopia lentis (Loeys 2001 PMID11700157, Comeglio 2002 PMID 12446365, Korkko 2002 PMID11826022, Ades 2004 15054843, Vanita 2007 18079676, Stheneur 2009 PMID 19293843). This variant segregated with isolated ectopia lentis in >10 family members from 2 different families (Ades 2004 PMID 15054843, Vanita 2007 PMID 18079676). This variant is absent from large population studies and has been reported by multiple laboratories as pathogenic in ClinVar (Variant ID:16461). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, this variant is predicted to affect a cysteine residue. Cysteine in the FBN1 gene is reported to have important functional relevance; variants that involve a cysteine residue are reported to be particularly significant (Dietz, PMID: 20301510). In summary, this variant is classified as pathogenic based on presence of affected individuals, segregation data, absence from controls, and predicted variant impact to the protein.
Invitae	RCV000631968	SCV000753071	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-11	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 240 of the FBN1 protein (p.Arg240Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ectopia lentis and/or Marfan syndrome (PMID: 11700157, 11826022, 15054843, 17657824, 18079676, 19293843, 20564469). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16461). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	RCV000017924	SCV000897654	likely pathogenic	Marfan syndrome	2018-11-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170326	SCV001332897	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-04-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001170326	SCV002668532	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-08-03	criteria provided, single submitter	clinical testing	The p.R240C pathogenic mutation (also known as c.718C>T), located in coding exon 6 of the FBN1 gene, results from a C to T substitution at nucleotide position 718. The arginine at codon 240 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the hybrid module #01 domain. This alteration has been reported in association with classic Marfan syndrome (Loeys B et al. Arch Intern Med. 2001;161(20):2447-54; Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8; Stark VC. Genes (Basel). 2020 07;11(7)), and has been detected in multiple individuals with isolated ectopia lentis (Körkkö J et al. J Med Genet. 2002;39(1):34-41; Comeglio P et al. Br J Ophthalmol. 2002;86(12):1359-62; Biggin A et al. Hum Mutat. 2004;23(1):99; Aragon-Martin JA et al. Hum Mutat. 2010;31(8):E1622-31). In addition, this alteration has been reported to segregate with disease in multiple affected individuals with isolated ectopia lentis in one family (Edwards MJ. Am J Med Gen. 1994;53(1):65-71; Adès LC et al. Am J Med Genet A. 2004;126A(3):284-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000017924	SCV002768944	pathogenic	Marfan syndrome	2022-02-02	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 been reported infrequently (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 - Two alternative amino acid changes at the same position has been observed in gnomAD (v3) (highest allele count: 3 heterozygotes, 0 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times in ClinVar, and has also been reported in multiple patients with ectopia lentis and Marfan syndrome (PMID: 30838813, 34281902). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Neuberg Centre For Genomic Medicine, NCGM	RCV000017924	SCV005042745	pathogenic	Marfan syndrome		criteria provided, single submitter	clinical testing	The missense variant c.718C>Tp.Arg240Cys in FBN1 gene has been reported previously in heterozygous state in multiple individuals with Marfan syndrome and Chen Z, et al., 2022, Gong B, et al., 2019. The R240C variant introduces a cysteine residue within the TGF-binding protein domain 1 of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Studies have shown that missense variants in the FBN1 gene that substitute or produce cysteine are associated with a higher risk for ectopia lentis than other missense variants Faivre L, et al., 2007. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Arginine at position 240 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Arg240Cys in FBN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000017924	SCV000038203	pathogenic	Marfan syndrome	2010-03-17	no assertion criteria provided	literature only
OMIM	RCV000017925	SCV000056640	pathogenic	Ectopia lentis 1, isolated, autosomal dominant	2010-03-17	no assertion criteria provided	literature only
Center for Medical Genetics Ghent, University of Ghent	RCV000017924	SCV000787308	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing