rs1555398524

Positions:

• chr15-48487188-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4 PP2 PP3 PM2_Supporting PS4 PM1_Strong PM6_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000138.5 c.3476G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 1159 (p.Cys1159Tyr). This variant was found in a 2-year-old proband with thoracic aortic aneurysm (TAA), ectopia lentis, and a systemic score ≥ 7, which is a highly specific phenotype for Marfan syndrome (MFS) (PP4; UZG internal data). This variant has been reported 3 times in ClinVar as pathogenic (2) and of uncertain significance (1) (Variation ID: 547309). This variant has been identified in 4 other individuals meeting the revised Ghent criteria for a clinical diagnosis of MFS, as de novo in a neonate with severe TAA and a systemic score of 6, and in 2 additional individuals who did not meet diagnostic criteria either but have phenotypes strongly suggestive of MFS (PS4, PM6_supporting; PMIDs: 35831148, 31523900, 34628919; UZG, Mayo, & Invitae internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL = 0.981). The constraint z-score for missense variants affecting FBN1 is 8.2 (PP2; gnomAD v4.1.0). 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: PS4, PM1_strong, PP2, PP3, PP4, PM2_supporting, PM6_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA392325981/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 ENST00000316623.10 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.64

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.

• 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.
• PM6: 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/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3476G>A	p.Cys1159Tyr	missense_variant	29/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3476G>A	p.Cys1159Tyr	missense_variant	28/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3476G>A	p.Cys1159Tyr	missense_variant	29/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2 Uncertain:1

Pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Aug 22, 2024	NM_000138.5 c.3476G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 1159 (p.Cys1159Tyr). This variant was found in a 2-year-old proband with thoracic aortic aneurysm (TAA), ectopia lentis, and a systemic score ≥ 7, which is a highly specific phenotype for Marfan syndrome (MFS) (PP4; UZG internal data). This variant has been reported 3 times in ClinVar as pathogenic (2) and of uncertain significance (1) (Variation ID: 547309). This variant has been identified in 4 other individuals meeting the revised Ghent criteria for a clinical diagnosis of MFS, as de novo in a neonate with severe TAA and a systemic score of 6, and in 2 additional individuals who did not meet diagnostic criteria either but have phenotypes strongly suggestive of MFS (PS4, PM6_supporting; PMIDs: 35831148, 31523900, 34628919; UZG, Mayo, & Invitae internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL = 0.981). The constraint z-score for missense variants affecting FBN1 is 8.2 (PP2; gnomAD v4.1.0). 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: PS4, PM1_strong, PP2, PP3, PP4, PM2_supporting, PM6_supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 12, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1159 of the FBN1 protein (p.Cys1159Tyr). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys1159 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 34628919; Invitae), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). 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. ClinVar contains an entry for this variant (Variation ID: 547309). This missense change has been observed in individuals with Marfan syndrome (PMID: 34628919; Invitae). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-9.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.98
MutPred		0.99		Gain of catalytic residue at C1159 (P = 0.0464);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3

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: rs1555398524; hg19: chr15-48779385;