rs397515863

Variant names:

• chr15-48411228-T-C
• rs397515863
• NM_000138.5:c.8378A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP2 PP3 PP4 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.8378A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 2793 (p.Tyr2793Cys), located within the C-terminal region of the protein. This variant was found in a proband with thoracic aortic dissection and a systemic score >7, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported three times in ClinVar: once as likely pathogenic, 2 times as uncertain significance (Variation ID: 42443). This variant has also been identified in at least 1 individual with a clinical diagnosis of MFS, as well as in individuals with clinical features of MFS (PMID 17663468, 34916231, 37558401, Invitae ClinVar, PS4_Moderate). A different missense variant at this position, c.8377T>C p.Tyr2793His, has previously been reported in individuals with MFS and/or MFS-related features (PMID 21542060, ClinVar), however the p.Tyr2793His variant has not yet been reviewed the FBN1 Variant Curation Expert Panel. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.967, PP3). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). 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: PS4_Moderate, PM2_Sup, PP2, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA017709/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 7.99
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: 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.8378A>G	p.Tyr2793Cys	missense_variant	Exon 66 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.8378A>G	p.Tyr2793Cys	missense_variant	Exon 65 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.8378A>G	p.Tyr2793Cys	missense_variant	Exon 66 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:3

Jan 02, 2025

Department of Laboratory Medicine and Genetics, Samsung Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NM_000138.5:c.8378A>G is considered to be rare in the general population database (gnomAD v2.1.1). This variant is predicted to be deleterious by in-silico analysis (REVEL). This variant is located in functional domains. This variant was found in a patient with Marfan syndrome meeting Ghent criteria (PMID: 17253931). According to the ClinGen guidance for PP1/BS4 and PP4 criteria (PMID: 38103548), PP4 with weighted strength was applied. In summary, this variant was classified as a pathogenic variant for Marfan syndrome (PM1, PP2, PP3, PP4 with weighted strength, PM2_P). -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2024

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_00138 c.8378A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 2793 (p.Tyr2793Cys), located within the C-terminal region of the protein. This variant was found in a proband with thoracic aortic dissection and a systemic score >7, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported three times in ClinVar: once as likely pathogenic, 2 times as uncertain significance (Variation ID: 42443). This variant has also been identified in at least 1 individual with a clinical diagnosis of MFS, as well as in individuals with clinical features of MFS (PMID 17663468, 34916231, 37558401, Invitae ClinVar, PS4_Moderate). A different missense variant at this position, c.8377T>C p.Tyr2793His, has previously been reported in individuals with MFS and/or MFS-related features (PMID 21542060, ClinVar), however the p.Tyr2793His variant has not yet been reviewed the FBN1 Variant Curation Expert Panel. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.967, PP3). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). 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: PS4_Moderate, PM2_Sup, PP2, PP3, PP4. -

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

Sep 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr2793 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 21542060), which suggests that this may be a clinically significant amino acid residue. 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: 42443). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 17253931; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2793 of the FBN1 protein (p.Tyr2793Cys). -

not specified Uncertain:1

Feb 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.72	D
PhyloP100		8.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.94
MutPred		0.83		Loss of stability (P = 0.0711);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
Mutation Taster		=11/89	disease causing

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: rs397515863; hg19: chr15-48703425;