rs363811

Positions:

• chr15-48421982-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4 PP1_Strong PP4 PP2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000138.5 c.7540G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine acid by arginine at amino acid 2514 (p.Gly2514Arg), located within a calcium binding EGF-like (cbEGF) domain of the protein. This variant was found in a proband with thoracic aortic aneurysm and ectopia lentis which is a highly specific phenotype for Marfan syndrome (internal data-Bichat) (PP4). This variant has been reported in at least 4 individuals with thoracic aortic aneurysm and/or clinical features of Marfan syndrome (PMID 26272055, 19720936, 11875032, Laboratory for Molecular Medicine ClinVarentry), and in at least 3 individuals clinically diagnosed with Marfan syndrome (PMID 33483584, 28468757, Rurali et al. 2019) (PS4). It was also found to segregate with the disease in at least 5 affected family members from multiple families (Rurali et al. 2019, Laboratory for Molecular Medicine ClinVar entry, internal data) (PP1_Strong). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.945) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_Strong, PM2_Sup, PP2, PP3, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA017250/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10 U:4
• Conservation: PhyloP100: 7.91

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

FBN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.7540G>A	p.Gly2514Arg	missense_variant	61/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.7540G>A	p.Gly2514Arg	missense_variant	60/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.7540G>A	p.Gly2514Arg	missense_variant	61/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:3 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Sep 28, 2023	The NM_000138.5 c.7540G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine acid by arginine at amino acid 2514 (p.Gly2514Arg), located within a calcium binding EGF-like (cbEGF) domain of the protein. This variant was found in a proband with thoracic aortic aneurysm and ectopia lentis which is a highly specific phenotype for Marfan syndrome (internal data-Bichat) (PP4). This variant has been reported in at least 4 individuals with thoracic aortic aneurysm and/or clinical features of Marfan syndrome (PMID 26272055, 19720936, 11875032, Laboratory for Molecular Medicine ClinVarentry), and in at least 3 individuals clinically diagnosed with Marfan syndrome (PMID 33483584, 28468757, Rurali et al. 2019) (PS4). It was also found to segregate with the disease in at least 5 affected family members from multiple families (Rurali et al. 2019, Laboratory for Molecular Medicine ClinVar entry, internal data) (PP1_Strong). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.945) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_Strong, PM2_Sup, PP2, PP3, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Sep 12, 2022	PM2, PP2, PP3, PP5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 15, 2015	- -

not provided Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	FBN1: PS4, PM1, PM2, PM5, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2021	The FBN1 c.7540G>A; p.Gly2514Arg variant (rs363811) is reported in the literature in several individuals affected with Marfan syndrome or thoracic aortic aneurysm/dissection (Guo 2015, Ng 2002, Pilop 2009, Rurali 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 2514 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.945). However, due to limited information, the clinical significance of the p.Gly2514Arg variant is uncertain at this time. References: Guo J et al. Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD. Sci Rep. 2015 Aug 14;5:13115. PMID: 26272055. Ng PC and Henikoff S. Accounting for human polymorphisms predicted to affect protein function. Genome Res. 2002 Mar;12(3):436-46. PMID: 11875032. Pilop C et al. Proteomic analysis in aortic media of patients with Marfan syndrome reveals increased activity of calpain 2 in aortic aneurysms. Circulation. 2009 Sep 15;120(11):983-91. PMID: 19720936. Rurali E et al. Soluble EMMPRIN levels discriminate aortic ectasia in Marfan syndrome patients. Theranostics. 2019 Apr 12;9(8):2224-2234. PMID: 31149040. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 25, 2020	PS4, PM2_supporting, PP2, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located in a cb-EGF-like domain at a glycine residue that is highly conserved across other similarly structured domains in the fibrillin-1 protein; This variant is associated with the following publications: (PMID: 24941995, 31227806, 19720936, 26272055, 11875032, 19561590, 33824467, 12938084, 33483584) -

Isolated thoracic aortic aneurysm Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Vascular Biology, Beijing Anzhen Hospital

Sep 01, 2018

- -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 24, 2022

Variant summary: FBN1 c.7540G>A (p.Gly2514Arg) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) 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 251264 control chromosomes (gnomAD). c.7540G>A has been reported in individuals diagnosed with Marfan Syndrome with aortic/cardiovascular phenotypes and without ocular phenotypes (example: Pilop_2009, Franken_2017, and Gezdirici_2021). At-least one individual is reported with sporadic thoracic aortic aneurysm and dissection (example: Guo_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3), Pathogenic (n=1) and Likely Pathogenic (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

FBN1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The FBN1 c.7540G>A variant is predicted to result in the amino acid substitution p.Gly2514Arg. This variant was reported in multiple individuals with Marfan syndrome (see for example - Ng et al. 2002. PubMed ID: 11875032; Guo et al. 2015. PubMed ID: 26272055; Gezdirici et al. 2021. PubMed ID: 33483584). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic by multiple laboratories including the ClinGen FBN1 Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/178034/). This variant is interpreted as pathogenic. -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2514 of the FBN1 protein (p.Gly2514Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with FBN1-related conditions (PMID: 11875032, 19720936, 26272055). ClinVar contains an entry for this variant (Variation ID: 178034). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 22, 2013

The Gly2514Arg variant in FBN1 has been reported in two individuals with Marfan syndrome (Ng 2002, Kumar 2009, Pilop 2009). In addition, this variant has been i dentified in 0.6% (3/336) of Asian chromosomes, 0.6% (1/180) of Luhya Kenyan chr omosomes, 2% (2/98) of Mexican chromosomes, and 0.6% (1/176) of Tuscan chromosom es by the HapMap Project (dbSNP rs363811). Computational analyses (biochemical a mino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly2514Arg variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. Furthermore, this variant has segre gated between a mother and daughter with clinical features of Marfan syndrome (L MM unpublished data), suggesting a pathogenic role. In summary, due to the confl icting information available, additional studies are needed to fully assess the clinical significance of the Gly2514Arg variant. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2015

The p.G2514R variant (also known as c.7540G>A), located in coding exon 60 of the FBN1 gene, results from a G to A substitution at nucleotide position 7540. The glycine at codon 2514 is replaced by arginine, an amino acid with dissimilar properties.In one study,this variant was reported in a individual affected withMarfansyndrome based on personal communication with investigator P.Oefner (Ng PC et al,Genome Res.2002 Mar; 12(3):436-46). This variant was alsoreported in a 22 year old male Chinese presented with thoracic aortic aneurysms, aortic regurgitation, mitral valve regurgitation and tricuspid valve regurgitation (Guo J et al,Sci Rep2015; 5:13115).This variant was previously reported in the SNPDatabase as rs363811. <span style="font-family:arial,sans-serif; font-size:10pt">This variant was not reported in population based cohorts in the following databases: NHLBIExomeSequencing Project (ESP)and 1000 Genomes Project. In the ESP, this variant was not observed in <span style="color:#000000"><span style="font-family:arial,sans-serif; font-size:10pt">6494<span style="font-family:arial,sans-serif; font-size:10pt">samples (<span style="font-family:arial,sans-serif; font-size:10pt">12988<span style="font-family:arial,sans-serif; font-size:10pt"><span style="color:#000000"> alleles) with coverage at this position.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. <br /> -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Vest4		0.96
MutPred		0.99		Loss of ubiquitination at K2510 (P = 0.0415);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs363811; hg19: chr15-48714179; COSMIC: COSV57326105;