15-48437011-T-C

Variant names:

• chr15-48437011-T-C
• rs113080385
• NM_000138.5:c.6446A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP2 PP3 PP4 PM2_Supporting PS4 PS2 PM1

This summary comes from the ClinGen Evidence Repository: NM_000138.5 c.6446A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine amino acid 2149 (p.Tyr2149Cys). This variant has been identified in at least 13 individuals with features suggestive of, or consistent with, Marfan syndrome (MFS), including four patients meeting clinical diagnostic criteria for MFS, seven with thoracic aortic aneurysm or dissection (TAAD) with or without additional features of MFS, and two with unspecified clinical suspicion of MFS (PS4, PP4; Johns Hopkins, University of Texas-Houston, LMM, & Invitae internal data; PMIDs: 24793577, 27611364, 37684520, 31098894). The variant was found to be de novo in five of these patients, including three (maternity/paternity assumed) with phenotypes consistent with, but not highly specific to, FBN1, one (maternity/paternity assumed) with TAAD and borderline systemic involvement, and one (maternity/paternity confirmed) with a non-specific and genetically heterogeneous phenotype of TAAD and mitral valve prolapse (PS2; Johns Hopkins & Invitae internal data; PMIDs: 31098894, 37684520). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1, 3.1.2, 4.0.0). This variant introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges and occurs at a conserved residue in a critical calcium-binding site within a calcium-binding EGF-like domain (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.900). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; gnomAD v4.0.0). 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: PS2, PS4, PM1, PP2, PP3, PP4, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA016465/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 4.41
• Publications: 4 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 14 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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	c.6446A>G	p.Tyr2149Cys	missense_variant	Exon 53 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6446A>G	p.Tyr2149Cys	missense_variant	Exon 52 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6446A>G	p.Tyr2149Cys	missense_variant	Exon 53 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:4

Aug 22, 2024

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000138.5 c.6446A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine amino acid 2149 (p.Tyr2149Cys). This variant has been identified in at least 13 individuals with features suggestive of, or consistent with, Marfan syndrome (MFS), including four patients meeting clinical diagnostic criteria for MFS, seven with thoracic aortic aneurysm or dissection (TAAD) with or without additional features of MFS, and two with unspecified clinical suspicion of MFS (PS4, PP4; Johns Hopkins, University of Texas-Houston, LMM, & Invitae internal data; PMIDs: 24793577, 27611364, 37684520, 31098894). The variant was found to be de novo in five of these patients, including three (maternity/paternity assumed) with phenotypes consistent with, but not highly specific to, FBN1, one (maternity/paternity assumed) with TAAD and borderline systemic involvement, and one (maternity/paternity confirmed) with a non-specific and genetically heterogeneous phenotype of TAAD and mitral valve prolapse (PS2; Johns Hopkins & Invitae internal data; PMIDs: 31098894, 37684520). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1, 3.1.2, 4.0.0). This variant introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges and occurs at a conserved residue in a critical calcium-binding site within a calcium-binding EGF-like domain (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.900). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; gnomAD v4.0.0). 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: PS2, PS4, PM1, PP2, PP3, PP4, PM2_supporting. -

Apr 10, 2023

deCODE genetics, Amgen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

The p.(Tyr2149Cys) variant occurred de novo in an individual diagnosed with Marfan syndrome, maternity and paternity confirmed. Applied ACMG criteria: PS2, PM2, PP2, PP4, PP5_strong -

Dec 03, 2018

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr2149Cys variant in FBN1 has previously been reported in at least 10 individuals: 3 individuals with aortopathy (Yang 2016 PMID: 27611364, Invitae Personal Communication 2023), 3 probands with clinical suspicion for Marfan syndrome (Lerner-Ellis 2014 PMID: 24793577, Invitae Personal Communication 2023), and 4 de novo occurrences in individuals with aortic aneurysm/dissection with or without additional features of Marfan syndrome (Li 2019 PMID: 31098894, Sulem 2022, Invitae Personal Communication 2023). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 42402). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant lies near the calcium binding site of the cbEGF domain, in which other pathogenic calcium binding site-disrupting alterations are present (Downing 1996 PMID: 8653794, Vollbrandt 2004 PMID: 15161917). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM1, PM6, PS4. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Feb 17, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y2149C variant (also known as c.6446A>G), located in coding exon 52 of the FBN1 gene, results from an A to G substitution at nucleotide position 6446. The tyrosine at codon 2149 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #32 domain. This variant was detected in an 11 year old female referred for genetic testing due to suspected Marfan syndrome; however, it was unclear if this individual met diagnostic criteria, and clinical details were not provided (Lerner-Ellis JP et al. Mol Genet Metab. 2014;112:171-6). Internal structural analysis indicates this alteration eliminates a highly conserved aromatic residue near the calcium binding site of the cbEGF domain 32, in which pathogenic calcium binding site-disrupting alterations are present (Downing AK et al. Cell. 1996;85(4):597-605). The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Jan 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2149 of the FBN1 protein (p.Tyr2149Cys). 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: 24793577, 27611364, 31098894; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 42402). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		4.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.67
MutPred		0.91		Gain of disorder (P = 0.0452);
MVP		0.92
MPC		1.5
ClinPred		1.0	D
GERP RS		5.8
Mutation Taster		=11/89	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: rs113080385; hg19: chr15-48729208;