rs886038795

Positions:

• chr15-48411118-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4 PM2_Supporting PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.8488C>T, is a nonsense variant in FBN1 that occurs in the last exon of the gene and is not expected to undergo nonsense-mediated decay but is expected to disrupt the last 42 amino acids of the protein. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). 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, PMID 29875124, PP4). This variant has been reported twice in ClinVar, once as pathogenic and once as uncertain significance (Variation ID: 263414). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). 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: PVS1_Strong, PM2_Sup, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA10587783/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 ENST00000316623.10 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 3.52

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 6 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.8488C>T	p.Gln2830Ter	stop_gained	66/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.8488C>T	p.Gln2830Ter	stop_gained	65/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.8488C>T	p.Gln2830Ter	stop_gained	66/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Aug 22, 2024	The NM_00138 c.8488C>T, is a nonsense variant in FBN1 that occurs in the last exon of the gene and is not expected to undergo nonsense-mediated decay but is expected to disrupt the last 42 amino acids of the protein. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). 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, PMID 29875124, PP4). This variant has been reported twice in ClinVar, once as pathogenic and once as uncertain significance (Variation ID: 263414). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). 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: PVS1_Strong, PM2_Sup, PP4 -
Uncertain significance, 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

Feb 29, 2020

This variant disrupts the C-terminus of the FBN1 protein. Other variant(s) that disrupt this region (p.Gln2867*) have been determined to be pathogenic (PMID: 19293843). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 263414). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FBN1 gene (p.Gln2830*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acids of the FBN1 protein. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D
Vest4		0.76
GERP RS		5.0

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: rs886038795; hg19: chr15-48703315;