rs137854485

Positions:

• chr15-48515402-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS2_Supporting PP2 PM2_Supporting PM1 PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: NM_00138 c.1453C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 485 (p.Arg484Cys). This variant has been identified in the literature in at least seven probands with features consistent with or suggestive of Marfan syndrome including thoracic aortic aneurysm and dissection (TAAD) with or without additional features (PS4; PMIDs: 16342915, 19293843, 24793577, 30485715). It was found in the homozygous state in two cousins with bilateral ectopia lentis (EL) and additional features of Marfan syndrome; of note, in both instances the variant was inherited from mildly affected or apparently unaffected heterozygous parents (PMID:17568394). It was identified in trans with a different FBN1 pathogenic variant in three siblings with isolated EL (Bichat internal data); clinical information for the heterozygous parents was not available. The variant has also been identified in the heterozygous state in 5 additional internal probands diagnosed with TAAD with or without systemic features (UZG, Johns Hopkins University, Bichat, & University of Tokyo internal data). It has been found to segregate in the heterozygous state with features of Marfan syndrome in at least 19 individuals among five different families (PP1_strong; PMID:30485715; Johns Hopkins & Bichat internal data). It has been identified as de novo once with confirmed maternity/paternity in an internal proband with a non-specific phenotype (PS2_supporting; PMID:19293843; UZG internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis are unclear about the variant’s predicted impact on the protein’s structure or function. 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, PM1, PS2_supporting, PM2_supporting, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA012160/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 2.16

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.1453C>T	p.Arg485Cys	missense_variant	12/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1453C>T	p.Arg485Cys	missense_variant	11/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1453C>T	p.Arg485Cys	missense_variant	12/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Nov 16, 2023	NM_00138 c.1453C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 485 (p.Arg484Cys). This variant has been identified in the literature in at least seven probands with features consistent with or suggestive of Marfan syndrome including thoracic aortic aneurysm and dissection (TAAD) with or without additional features (PS4; PMIDs: 16342915, 19293843, 24793577, 30485715). It was found in the homozygous state in two cousins with bilateral ectopia lentis (EL) and additional features of Marfan syndrome; of note, in both instances the variant was inherited from mildly affected or apparently unaffected heterozygous parents (PMID: 17568394). It was identified in trans with a different FBN1 pathogenic variant in three siblings with isolated EL (Bichat internal data); clinical information for the heterozygous parents was not available. The variant has also been identified in the heterozygous state in 5 additional internal probands diagnosed with TAAD with or without systemic features (UZG, Johns Hopkins University, Bichat, & University of Tokyo internal data). It has been found to segregate in the heterozygous state with features of Marfan syndrome in at least 19 individuals among five different families (PP1_strong; PMID: 30485715; Johns Hopkins & Bichat internal data). It has been identified as de novo once with confirmed maternity/paternity in an internal proband with a non-specific phenotype (PS2_supporting; PMID: 19293843; UZG internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis are unclear about the variant’s predicted impact on the protein’s structure or function. 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, PM1, PS2_supporting, PM2_supporting, PP2. -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 29, 2019	The p.R485C pathogenic mutation (also known as c.1453C>T), located in coding exon 11 of the FBN1 gene, results from a C to T substitution at nucleotide position 1453. The arginine at codon 485 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the EGF-like #4 domain. This mutation has been reported in multiple individuals with Marfan syndrome (MFS) and Marfan-like findings, including one reported de novo MFS case (Baumgartner C et al. Methods Inf Med, 2005;44:487-97; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8; Hung CC et al. Ann. Hum. Genet., 2009 Nov;73:559-67; Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6). Cosegregation in affected family members has been reported in two families with thoracic aortic aneurysms, abdominal aortic aneurysms, and other clinical findings consistent with MFS (Overwater E et al. Mol Genet Genomic Med, 2018 Nov;[Epub ahead of print]). In a consanguineous family, this mutation was detected as homozygous in two cousins with MFS, while their heterozygous parents were described as not having symptoms of MFS (de Vries BB et al. Eur. J. Hum. Genet., 2007 Sep;15:930-5). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Marfan syndrome, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 485 of the FBN1 protein (p.Arg485Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 16342915, 17568394, 19839986, 24793577, 30485715, 30739908). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16466). 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. 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

Feb 15, 2018

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.50	D
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.020	D
Vest4		0.90
MutPred		0.76		Loss of disorder (P = 0.1379);
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs137854485; hg19: chr15-48807599;