15-48513656-C-G

Position:

• chr15-48513656-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1_Strong PP2 PP3 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000138.5(FBN1):c.1481G>C (p.Cys494Ser)NM_00138 c.1481G>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by serine at amino acid 494 (p.Cys494Ser). This variant was found in two probands, one with isolated thoracic aortic aneurysm and dissection (TAAD) and one with TAAD and systemic features of Marfan syndrome (PS4_supporting; PMID:32209317; UZG internal data). This variant has been reported twice in ClinVar as likely pathogenic and once as of uncertain significance (Variation ID: 502478). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium binding EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys494Tyr, p.Cys494Trp, p.Cys494Phe). Computational prediction tools and conservation analysis strongly support that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_supporting, PP2, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA392342805/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.57

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 Likely_pathogenic. Variant got 8 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.
• 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.1481G>C	p.Cys494Ser	missense_variant	13/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1481G>C	p.Cys494Ser	missense_variant	12/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.1481G>C	p.Cys494Ser	missense_variant	13/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Nov 16, 2023	NM_000138.5(FBN1):c.1481G>C (p.Cys494Ser) NM_00138 c.1481G>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by serine at amino acid 494 (p.Cys494Ser). This variant was found in two probands, one with isolated thoracic aortic aneurysm and dissection (TAAD) and one with TAAD and systemic features of Marfan syndrome (PS4_supporting; PMID: 32209317; UZG internal data). This variant has been reported twice in ClinVar as likely pathogenic and once as of uncertain significance (Variation ID: 502478). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium binding EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys494Tyr, p.Cys494Trp, p.Cys494Phe). Computational prediction tools and conservation analysis strongly support that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_supporting, PP2, PP3, PM2_supporting. -
Likely 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys494 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 28973303), 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: 502478). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 494 of the FBN1 protein (p.Cys494Ser). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.2	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.97
MutPred		0.96		Loss of stability (P = 0.0723);
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1057518881; hg19: chr15-48805853;