Submissions for variant NM_000138.5(FBN1):c.364C>T (p.Arg122Cys)

dbSNP: rs137854467

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029732	SCV000052385	pathogenic	Marfan syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
GeneDx	RCV000181647	SCV000233950	pathogenic	not provided	2022-01-18	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 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); Reported in ClinVar by several laboratories as pathogenic (ClinVar Variant ID# 16440); This variant is associated with the following publications: (PMID: 19293843, 25053872, 22772377, 19839986, 12446365, 21932315, 21895641, 11700157, 19089573, 17679947, 9452085, 24161884, 24199744, 32123317, 8040326, 34957211, 12938084, 31730815)
Invitae	RCV001201375	SCV000544955	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-13	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 122 of the FBN1 protein (p.Arg122Cys). 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: 8040326, 9452085, 11700157, 12446365, 17679947, 21895641, 21932315, 22772377, 25053872). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16440). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001798007	SCV000738914	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2017-07-28	criteria provided, single submitter	clinical testing	The p.R122C pathogenic mutation (also known as c.364C>T), located in coding exon 4 of the FBN1 gene, results from a C to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the EGF-like #02 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 particular alteration has been detected in numerous unrelated individuals with ectopia lentis (EL) and/or Marfan syndrome (MFS) (e.g., Loeys B et al. Arch. Intern. Med. 2001;161:2447-54; Comeglio P et al. Br J Ophthalmol. 2002;86:1359-62; Jin C et al. Mol. Vis. 2007;13:1280-4; Hung CC et al. Ann. Hum. Genet. 2009;73:559-67; Li J et al. Mol. Vis. 2014;20:1017-24). In addition, this alteration has been reported to segregate with disease in three families (Ståhl-Hallengren C et al. J. Clin. Invest. 1994;94:709-13; Black C et al. Hum. Mutat. 1998;Suppl 1:S198-200; Zadeh N et al. Am. J. Med. Genet. A. 2011;155A:2661-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626614	SCV000747315	pathogenic	High palate; Arachnodactyly; Lens subluxation; Aortic dissection	2017-01-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000181647	SCV000927817	pathogenic	not provided	2018-07-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000178	SCV001156669	pathogenic	not specified	2018-08-13	criteria provided, single submitter	clinical testing	The FBN1 c.364C>T; p.Arg122Cys variant (rs137854467) has been reported in multiple families with clinical symptoms suggestive of Marfan syndrome, and is strongly associated with ectopia lentis (Black 1998, Comeglio 2002, Jin 2007, Loeys 2001, Stahl-Hallengran 1994). It is reported in ClinVar as pathogenic (Variation ID: 16440) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The variant changes an arginine in an EGF-like domain into a cysteine residue, which meets the revised Ghent nosology criteria of a causative Marfan syndrome variant (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Black C et al. Correlation of a recurrent FBN1 mutation (R122C) with an atypical familial Marfan syndrome phenotype. Hum Mutat. 1998; Suppl 1:S198-200. Comeglio P et al. Identification of FBN1 gene mutations in patients with ectopia lentis and marfanoid habitus. Br J Ophthalmol. 2002; 86(12):1359-62. Jin C et al. Novel FBN1 mutations associated with predominant ectopia lentis and marfanoid habitus in Chinese patients. Mol Vis. 2007; 13:1280-4. Loeys B et al. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001; 2001 Nov 12;161(20):2447-54. Loeys B et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010; 47(7):476-85. Stahl-Hallengren C et al. An extra cysteine in one of the non-calcium-binding epidermal growth factor-like motifs of the FBN1 polypeptide is connected to a novel variant of Marfan syndrome. J Clin Invest. 1994; 94(2):709-13.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000181647	SCV001450112	pathogenic	not provided	2014-11-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798007	SCV002041974	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-05-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496395	SCV002811496	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	2021-08-23	criteria provided, single submitter	clinical testing
OMIM	RCV000017902	SCV000038181	pathogenic	Marfan syndrome, atypical	1994-08-01	no assertion criteria provided	literature only
Center for Medical Genetics Ghent, University of Ghent	RCV000029732	SCV000786986	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing