rs1555398511

Positions:

• chr15-48487107-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4 PM1 PP2 PP3 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000138.5 c.3557A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by a cysteine at amino acid 1186 (p.Tyr1186Cys). It has been identified in at least five individuals with diagnoses or suspicion of Marfan syndrome including the following: a pediatric patient with bilateral ectopia lentis (EL), severe thoracic aortic aneurysm and dissection (TAAD), and a systemic score of 9; an adult patient with EL and a systemic score of 6; a patient with bilateral EL, TAAD, and systemic features; an individual reported to have Marfan syndrome without specific details provided; and an individual with bilateral EL, TAAD, retinal detachment, and systemic features (PS4; PMIDs: 31061752, 11933199; UZG, Bichat, & Invitae internal data). It was also found to segregate with Marfan syndrome in two other members of an aforementioned family (PP1; Bichat internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1 & v3.1.2). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.974). 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, PM1, PP1, PP2, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA392324980/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 6.19

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 10 ACMG points.

• 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.
• PP1: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3557A>G	p.Tyr1186Cys	missense_variant	29/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3557A>G	p.Tyr1186Cys	missense_variant	28/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3557A>G	p.Tyr1186Cys	missense_variant	29/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2

Likely pathogenic, 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	Dec 29, 2023	NM_000138.5 c.3557A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by a cysteine at amino acid 1186 (p.Tyr1186Cys). It has been identified in at least five individuals with diagnoses or suspicion of Marfan syndrome including the following: a pediatric patient with bilateral ectopia lentis (EL), severe thoracic aortic aneurysm and dissection (TAAD), and a systemic score of 9; an adult patient with EL and a systemic score of 6; a patient with bilateral EL, TAAD, and systemic features; an individual reported to have Marfan syndrome without specific details provided; and an individual with bilateral EL, TAAD, retinal detachment, and systemic features (PS4; PMIDs: 31061752, 11933199; UZG, Bichat, & Invitae internal data). It was also found to segregate with Marfan syndrome in two other members of an aforementioned family (PP1; Bichat internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1 & v3.1.2). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.974). 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, PM1, PP1, PP2, PP3, PM2_supporting. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 12, 2016

Variant summary: The FBN1 c.3557A>G (p.Tyr1186Cys) variant involves the alteration of a conserved nucleotide located in a conserved region within EGF-like #14. "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. In support of a deleterious effect of this variant, 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index) and the variant is absent in 120500 control chromosomes. The variant was detected in one classicial MFS patient in the literature (Stheneur_2009). Therefore, the variant was classified as a VUS - possibly pathogenic variant. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2019

This sequence change replaces tyrosine with cysteine at codon 1186 of the FBN1 protein (p.Tyr1186Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals with clinical features of Marfan syndrome (PMID: 19293843, Invitae). ClinVar contains an entry for this variant (Variation ID: 495594). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.97
MutPred		0.98		Loss of catalytic residue at P1190 (P = 0.1137);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.8

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: rs1555398511; hg19: chr15-48779304;