NM_000138.5:c.7540G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4PP2PM2_SupportingPS4PP1_Strong

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

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:12U:3

Conservation

PhyloP100: 7.91

Publications

7 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Marfan syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
Acromicric dysplasia
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
progeroid and marfanoid aspect-lipodystrophy syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
stiff skin syndrome
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Weill-Marchesani syndrome 2, dominant
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
geleophysic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated ectopia lentis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neonatal Marfan syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Weill-Marchesani syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ectopia lentis 1, isolated, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: G2P
Shprintzen-Goldberg syndrome
Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

FBN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.7540G>A	p.Gly2514Arg	missense_variant	Exon 61 of 66	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.7540G>A	p.Gly2514Arg	missense_variant	Exon 60 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.7540G>A	p.Gly2514Arg	missense_variant	Exon 61 of 66	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:4Uncertain:1

Sep 15, 2015

Blueprint Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 28, 2023

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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 -

Sep 12, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PP2, PP3, PP5 -

Jan 16, 2025

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense, heterozygous variant NM_000138.5:c.7540G>A p.(Gly2514Arg) in the gene FBN1 implicates an amino acid that is 100% conserved in vertebrates and is located in a functional domain. This variant is absent from gnomAD (v4.1.0) and has previously been reported numerous times in ClinVar as pathogenic, likely pathogenic and of uncertain significance. Pathogenic monoallelic variants in the FBN1 gene are associated with a spectrum of syndromes including Marfan syndrome, of autosomal dominant transmission (OMIM #154700). According to the available evidence, this variant is considered to be pathogenic. -

not provided

Pathogenic:3Uncertain:1

Mar 28, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 25, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PM2_supporting, PP2, PP3 -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FBN1: PS4, PM1, PM2, PM5, PP3 -

Jul 01, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Dec 30, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G2514R pathogenic mutation (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. This variant was reported in individual(s) with features consistent with Marfan syndrome and segregated with disease in at least one family (Ng PC et al. Genome Res, 2002 Mar;12:436-46; Guo J et al. Sci Rep, 2015 Aug;5:13115; Pilop C et al. Circulation, 2009 Sep;120:983-91; Rurali E et al. Theranostics, 2019 Apr;9:2224-2234; Gezdirici A et al. J Hum Genet, 2021 Jul;66:647-657; external communication; Ambry internal data). This variant alters a conserved residue in the calcium-binding consensus sequence of a cbEGF domain and is expected to disrupt FBN1 function (Handford PA et al. Nature. 1991; 351(6322):164-7). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Jensen SA et al. Structure, 2009 May;17:759-68; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

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

Pathogenic:1

Jul 02, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. c.7540G>A has been reported in individuals diagnosed with Marfan Syndrome with aortic/cardiovascular phenotypes and without ocular phenotypes (e.g. 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 very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11875032, 19720936, 26272055, 33483584, 28468757). ClinVar contains an entry for this variant (Variation ID: 178034). Based on the evidence outlined above, the variant was classified as pathogenic. -

Isolated thoracic aortic aneurysm

Pathogenic:1

Sep 01, 2018

Department of Vascular Biology, Beijing Anzhen Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

FBN1-related disorder

Pathogenic:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Aug 22, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

PhyloP100

7.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Vest4

0.96

MutPred

0.99

Loss of ubiquitination at K2510 (P = 0.0415);

MVP

0.98

MPC

1.6

ClinPred

1.0

GERP RS

5.9

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over