chr15-48489896-C-T

Variant names:

• chr15-48489896-C-T
• rs140593
• NM_000138.5:c.3037G>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.3037G>A​(p.Gly1013Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 U:1
• Conservation: PhyloP100: 7.90
• Publications: 20 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS1: Transcript NM_000138.5 (FBN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 10 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to Marfan syndrome, Weill-Marchesani syndrome 2, dominant, progeroid and marfanoid aspect-lipodystrophy syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, stiff skin syndrome, familial thoracic aortic aneurysm and aortic dissection, isolated ectopia lentis, ectopia lentis 1, isolated, autosomal dominant, Acromicric dysplasia, neonatal Marfan syndrome, Weill-Marchesani syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 15-48489896-C-T is Pathogenic according to our data. Variant chr15-48489896-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 177648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3037G>A	p.Gly1013Arg	missense_variant	Exon 25 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3037G>A	p.Gly1013Arg	missense_variant	Exon 24 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3037G>A	p.Gly1013Arg	missense_variant	Exon 25 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000566 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:8 Uncertain:1

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PS1, PP4 -

Feb 11, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 14, 2024

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: 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

- -

Aug 26, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated, PP2 supporting, PP3 supporting -

Jun 10, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 -

Aug 18, 2020

Human Genetics Unit, University Of Colombo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar classifies this variant as Pathogenic, 2 stars (reviewed Mar '25, 14 submissions of which 3 are from high confidence submitters) [PP5]. Equivalent variant chr15:48782093 C>G (Gly1013Arg) is classified Pathogenic by UniProt Variants [PS1]. Hot-spot of length 17 amino-acids has 21 missense/in-frame variants (6 pathogenic variants, 14 uncertain variants, and 1 benign variant), which qualifies as moderate pathogenic [PM1]. Variant not found in gnomAD exomes, with good gnomAD exomes coverage = 95.1 [PM2]. Multiple lines of In silico analyses supports that this variant has a deleterious effect on protein structure/function [PP3]. This variant was present in a patient who was diagnosed with early onset Marfan Syndrome [PP4]. In summary, this variant meets criteria to be classified as pathogenic based on ACMG/AMP guidelines: PS1, PM1, PM2, PP3, PP4, and PP5. -

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided Pathogenic:4

Nov 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); 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; This variant is associated with the following publications: (PMID: 14695540, 27437668, 34550612, 31061752, 33436942, 32198975, 7611299, 11175294, 10464652, 11700157, 16220557, 19002209, 22772377, 11780406, no PMID, 17701892, 10930463, 33495528, 21135753, 32679894, 29939511, 35058154, 12938084, 21784848) -

Nov 09, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jul 14, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Cardiovascular phenotype Pathogenic:1

Oct 15, 2021

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 27, 2025

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 1013 of the FBN1 protein (p.Gly1013Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 7611299, 10464652, 11175294, 11700157, 11780406, 14695540, 16220557, 19002209). ClinVar contains an entry for this variant (Variation ID: 177648). 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%. Experimental studies have shown that this missense change affects FBN1 function (PMID: 21784848). For these reasons, this variant has been classified as Pathogenic. -

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	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.065	T
Vest4		1.0
MutPred		0.72		Loss of ubiquitination at K1017 (P = 0.0821);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.6
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs140593; hg19: chr15-48782093;