Submissions for variant NM_000138.5(FBN1):c.3037G>A (p.Gly1013Arg)

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Total submissions: 12

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154235	SCV000203890	pathogenic	Marfan syndrome	2016-02-11	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Eurofins Ntd Llc (ga)	RCV000181476	SCV000228190	pathogenic	not provided	2014-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000181476	SCV000233779	pathogenic	not provided	2021-03-11	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14695540, 27437668, 31061752, 33436942, 32198975, 21784848, 7611299, 11175294, 10464652, 11700157, 16220557, 19002209, 22772377, 11780406, no PMID, 17701892, 10930463, 33495528, 21135753, 32679894)
Invitae	RCV000631914	SCV000753017	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-11	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 177648). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 7611299, 10464652, 11175294, 11700157, 11780406, 14695540, 16220557, 19002209). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1013 of the FBN1 protein (p.Gly1013Arg). Experimental studies have shown that this missense change affects FBN1 function (PMID: 21784848). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000181476	SCV000928045	pathogenic	not provided	2018-11-09	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000154235	SCV002025558	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
DASA	RCV000154235	SCV002526390	pathogenic	Marfan syndrome	2022-06-10	criteria provided, single submitter	clinical testing	The c.3037G>A;p.(Gly1013Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 177648; PMID: 21784848; 19002209; 16220557; 14695540; 11780406) - PS4.Same amino acid change as a previously established Pathogenic variant regardless of nucleotide change (ClinVar ID: 16455; PMID: 11175294) - PS1.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21784848) - PS3_moderate. This variant is not present in population databases:rs140593, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Ambry Genetics	RCV002433672	SCV002753944	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-07-14	criteria provided, single submitter	clinical testing	The p.G1013R pathogenic mutation (also known as c.3037G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 3037. The glycine at codon 1013 is replaced by arginine, an amino acid with dissimilar properties, and is located in the TGFBP #03 domain. This alteration has been reported in numerous individuals with a clinical diagnosis of Marfan syndrome, including as a de novo alteration in an individual with neonatal Marfan syndrome with a severe, atypical presentation (Nijbroek G et al. Am J Hum Genet, 1995 Jul;57:8-21; Biggin A et al. Hum Mutat, 2004 Jan;23:99; Ardhanari M et al. J Pediatr Genet, 2019 Jun;8:86-90; Rommel K et al. Hum Mutat, 2005 Dec;26:529-39; Stark VC et al. Genes (Basel), 2020 07;11; Arnaud P et al. Genet Med, 2021 05;23:865-871). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000154235	SCV003807791	pathogenic	Marfan syndrome	2022-08-26	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated, PP2 supporting, PP3 supporting
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000154235	SCV004034104	pathogenic	Marfan syndrome	2023-07-01	criteria provided, single submitter	research
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000154235	SCV004046020	pathogenic	Marfan syndrome		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with Marfan syndrome (PMID: 7611299, 11175294, 14695540, 10464652, 11700157, 11780406, 16220557, 19002209). It falls in a hotspot for a severe early onset cardiovascular phenotype and has been reported in unrelated patients with atypically severe manifestations (PMID: 7611299, 32198975). Experimental studies have shown that this variant affects the FBN1 protein by inducing the loss of heparin binding and enhancing the susceptibility to proteolysis (PMID: 21784848). It is absent from the gnomAD population database and thus is presumed to be rare. The c.3037G>A (p.Gly1013Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3037G>A (p.Gly1013Arg) variant is classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000154235	SCV000786914	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing

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