Submissions for variant NM_000138.5(FBN1):c.1948C>T (p.Arg650Cys)

dbSNP: rs193922185

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029702	SCV000052355	likely pathogenic	Marfan syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
GeneDx	RCV000493360	SCV000582280	pathogenic	not provided	2022-03-21	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 FBN-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 27353645, 17701892, 15161917, 21932315, 25900864, 29376001, 16677079, 4750422, 33844962, 12938084, 28941062)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507859	SCV000603634	pathogenic	not specified	2016-09-19	criteria provided, single submitter	clinical testing
Invitae	RCV000631908	SCV000753011	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-05	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 650 of the FBN1 protein (p.Arg650Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ectopia lentis (PMID: 21932315, 25900864). ClinVar contains an entry for this variant (Variation ID: 36042). 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.
Fulgent Genetics, Fulgent Genetics	RCV000763357	SCV000894047	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	2018-10-31	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000493360	SCV001450208	likely pathogenic	not provided	2017-02-23	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000029702	SCV002025522	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS5, PP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798013	SCV002041957	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-05-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001798013	SCV002722261	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-02-24	criteria provided, single submitter	clinical testing	The c.1948C>T (p.R650C) alteration is located in exon 16 (coding exon 15) of the FBN1 gene. This alteration results from a C to T substitution at nucleotide position 1948, causing the arginine (R) at amino acid position 650 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD), the FBN1 c.1948C>T alteration was not observed, with coverage at this position. This alteration has been reported in individuals and families with ectopia lentis, some of whom also had aortic findings (Zadeh, 2011; Zhang, 2015; Vatti, 2017). This amino acid position is highly conserved in available vertebrate species. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt, 2004). The p.R650C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000029702	SCV000786812	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing