15-48415695-C-T

Variant names:

• chr15-48415695-C-T
• rs111856492
• NM_000138.5:c.7892G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4 PP2 PP3 PM2_Supporting PS4_Moderate PM1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.7892G>A, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2631 (p.Cys2631Tyr). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported three times in ClinVar: once as pathogenic, once as likely pathogenic, and once as uncertain significance (Variation ID: 42436). This variant has also been identified in at least 2 individuals with clinical diagnosis of MFS as well as in individuals with clinical features of MFS (PMID 24793577, Invitae ClinVar, internal lab data; PS4_Mod). In one pediatric individual with MFS, this variant found to segregate in an affected sister and was found to be mosaic in the asymptomatic mother (internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be 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 (REVEL: 0.976, 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 pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PS4_Moderate, PM2_Sup, PP2, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA017451/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.91
• 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: Pathogenic. The variant received 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.
• 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.7892G>A	p.Cys2631Tyr	missense_variant	Exon 64 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.7892G>A	p.Cys2631Tyr	missense_variant	Exon 63 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.7892G>A	p.Cys2631Tyr	missense_variant	Exon 64 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2

Aug 22, 2024

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_00138 c.7892G>A, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2631 (p.Cys2631Tyr). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported three times in ClinVar: once as pathogenic, once as likely pathogenic, and once as uncertain significance (Variation ID: 42436). This variant has also been identified in at least 2 individuals with clinical diagnosis of MFS as well as in individuals with clinical features of MFS (PMID 24793577, Invitae ClinVar, internal lab data; PS4_Mod). In one pediatric individual with MFS, this variant found to segregate in an affected sister and was found to be mosaic in the asymptomatic mother (internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be 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 (REVEL: 0.976, 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 pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PS4_Moderate, PM2_Sup, PP2, PP3, PP4. -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jan 03, 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 missense change has been observed in individuals with Marfan syndrome (PMID: 24793577; Invitae). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2631 of the FBN1 protein (p.Cys2631Tyr). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 42436). 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. 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). -

not specified Uncertain:1

Feb 11, 2016

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	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.95
MutPred		0.93		Loss of methylation at K2630 (P = 0.0127);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
Mutation Taster		=0/100	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: rs111856492; hg19: chr15-48707892;