Submissions for variant NM_000138.5(FBN1):c.7606G>A (p.Gly2536Arg)

dbSNP: rs397515854

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035274	SCV000058922	pathogenic	Marfan syndrome	2006-10-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000181609	SCV000233912	pathogenic	not provided	2018-09-17	criteria provided, single submitter	clinical testing	p.Gly2536Arg (GGG>AGG): c.7606 G>A in exon 62 of the FBN1 gene (NM_000138.4)The G2536R mutation in the FBN1 gene has been reported in multiple individuals with Marfan syndrome (FBN1-UMD database). Subsequently, G2536R is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. Mutations in nearby residues (C2541F, C2535W) have been reported in association with Marfan syndrome , supporting the functional importance of this region of the protein. Furthermore, the G2536R mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, G2536R in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586498	SCV000695603	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2016-08-05	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.7606G>A (p.Gly2536Arg) variant located in a Ca2+ binding domain causing a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured here due to low reliability) predicting a damaging outcome. The variant of interest was not found in controls (ExAC, 1000 Gs, or ESP). The variant of interest has been reported in multiple affected individuals with varying phenotypes: MFS, MFS-like, and TAAD. In addition, a functional study (Robinson_2012) indicates the variant alterates splicing producing a 32 deletion transcript (<2% total product). Multiple reputable databases/clinical laboratories.Furthermore, mutations in nearby residues (C2541F, C2535W) have been reported in association with Marfan syndrome. Therefore, the variant of interest has been classified as "pathogenic."
Invitae	RCV000698696	SCV000827376	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2536 of the FBN1 protein (p.Gly2536Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FBN1-related conditions (PMID: 11524736, 16220557, 17657824, 24793577, 25907466, 26272055). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 42429). 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%. Studies have shown that this missense change results in altered splicing and introduces a premature termination codon (PMID: 21895641). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Centre of Medical Genetics, University of Antwerp	RCV000035274	SCV002025454	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP1, PP4
Ambry Genetics	RCV002390140	SCV002674419	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-06-02	criteria provided, single submitter	clinical testing	The p.G2536R pathogenic mutation (also known as c.7606G>A), located in coding exon 61 of the FBN1 gene, results from a G to A substitution at nucleotide position 7606. The glycine at codon 2536 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in subjects with features of Marfan syndrome and thoracic aortic aneurysm and dissection (TAAD) and has been reported as a de novo occurrence (Comeglio P et al. Hum. Mutat., 2001 Sep;18:251; Rommel K et al. Hum. Mutat., 2005 Dec;26:529-39; Robinson DO et al. Clin. Genet., 2012 Sep;82:223-31; Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6; Proost D et al. Hum. Mutat., 2015 Aug;36:808-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, RNA studies show this alteration has an aberrant impact on splicing (Robinson DO et al. Clin. Genet., 2012 Sep;82:223-31). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV002390140	SCV004240594	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-10-12	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000035274	SCV000787344	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing