Submissions for variant NM_000138.5(FBN1):c.8038C>T (p.Arg2680Cys)

dbSNP: rs794728283

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181625	SCV000233928	pathogenic	not provided	2022-02-28	criteria provided, single submitter	clinical testing	Reported in the literature in association with Marfan syndrome or suspected Marfan syndrome in multiple individuals, several of whom had ectopia lentis and skeletal features without aortic dilation (Grossfield et al., 1993; Palz et al., 2000; Comeglio et al., 2007; Jin et al., 2007; Arnaud et al., 2017), and in patients referred for genetic testing at GeneDx.; 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 into 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); This variant is associated with the following publications: (PMID: 17568394, 8653794, 9401003, 18615205, 15054843, 17657824, 27647783, 27582083, 17679947, 10756346, 27535533, 33059708, 31751304)
Ambry Genetics	RCV000770651	SCV000318734	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-12-18	criteria provided, single submitter	clinical testing	The p.R2680C variant (also known as c.8038C>T), located in coding exon 63 of the FBN1 gene, results from a C to T substitution at nucleotide position 8038. The arginine at codon 2680 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #43 domain. This variant has been reported in individuals with Marfan syndrome-like features, including ocular and skeletal findings and one reportedly de novo occurrence (Palz M et al. Am. J. Med. Genet., 2000 Mar;91:212-21; Comeglio P et al. Hum. Mutat., 2007 Sep;28:928). This variant was also described in an individual with Marfan syndrome who was a compound heterozygote with an additional FBN1 variant; her son was heterozygous for only p.R2680C and was reported to have ectopia lentis at two years old, with no additional clinical features of Marfan syndrome at that time (Arnaud P et al. J. Med. Genet., 2017 02;54:100-103). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000476927	SCV000544872	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-16	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 2680 of the FBN1 protein (p.Arg2680Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FBN1-related conditions and Marfan syndrome (PMID: 10756346, 12938084, 17657824, 27582083; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 200127). 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659584	SCV000781422	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770651	SCV000902109	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987427	SCV004803934	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.8038C>T (p.Arg2680Cys) results in a non-conservative amino acid change located in the EGF like domain (IPR001881) 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 249484 control chromosomes (gnomAD). c.8038C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (examples: Collod-Beroud_1998, Palz_2000, and Klemenzdottir_2024). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 37684520, 9399842, 10756346). ClinVar contains an entry for this variant (Variation ID: 200127). Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000659584	SCV000787392	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV000659584	SCV003915960	pathogenic	Marfan syndrome	2023-04-10	no assertion criteria provided	case-control	The p.(Arg2680Cys) variant was identified in a six-generation Marfan syndrome family in Iceland. There are 21 carriers of the variant in this family, either diagnosed with Marfan syndrome and/or show clinical features consistent with Marfan syndrome. Overall p.(Arg2680Cys) appears to result in mild Marfan syndrome, but a strong predisposition to the development of abdominal aortic aneurysms. The variant associates with increased height (p-value 5.65*10-8; SD 1.46) and thoracid aortic aneurysm (p-value 0.042; OR 23.3). Applied ACMG criteria: PS4, PM2, PP2, PP4Applied ACMG criteria: PS4, PM2, PP2, PP3, PP4, PP5_strong