15-48411280-G-A

Position:

• chr15-48411280-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS3 PS4 PP1_Strong PVS1_Strong PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.8326C>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 96 amino acids of the protein. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). In an in-vitro microfibril assay, this variant was reported to result in intracellular retention of the protein (PMID 24982166; PS3). This variant was found in a proband with aortic aneurysm and dissection, ectopia lentis, and skeletal features, who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data; PP4). This variant has been reported 10 times in ClinVar, nine as pathogenic and once as likely pathogenic (Variation ID: 16439). Several other probands with a clinical diagnosis of Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (internal lab data, PMID 9338581, 31098894, 31730815, 33059708, 25907466, 19293843, 34916231; PS4). In one individual with aortic dissection and myopia, this variant was reported to be de novo without confirmation of parental relationships (PMID 31098894; 0.25 points). In two families with MFS, this variant was found to segregate with disease in five affected family members (internal lab data; PP1_Strong). This variant is present in in 10/24982 (0.04%) of alleles tested from the Finnish population in gnomAD and did not pass the quality control criteria in the genome subset (PM2_Sup; https://gnomad.broadinstitute.org/ v2.1.1). 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: PVS1_Strong, PS4, PS3, PP1_Strong, PM2_Sup, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA017692/MONDO:0007947/022

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:11 U:1
• Conservation: PhyloP100: 8.16

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.8326C>T	p.Arg2776*	stop_gained	66/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.8326C>T	p.Arg2776*	stop_gained	65/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.8326C>T	p.Arg2776*	stop_gained	66/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251286 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461668 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74430

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 10, 2021	PVS1, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Jul 19, 2019	At our clinical center The p.R2776* variant was found in one family and one unrelated individual. This variant present in variouas individual studies reported by other submitters (ClinVar entry - Variation ID:16439), as well as present in population studies (C=0.00001 (1/121406, ExAC)). Functional study of the variant (PMID: 24982166) shows its pathogenic mechanism by linkage of the immature monomers, thus it behaves as a dominant-negative mutation, disrupting not only the mutant protein, but the normal one, which is synthesized from the unchanged allele. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1994	- -
Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2015	- -
Pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Aug 22, 2024	The NM_00138 c.8326C>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 96 amino acids of the protein. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). In an in-vitro microfibril assay, this variant was reported to result in intracellular retention of the protein (PMID 24982166; PS3). This variant was found in a proband with aortic aneurysm and dissection, ectopia lentis, and skeletal features, who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data; PP4). This variant has been reported 10 times in ClinVar, nine as pathogenic and once as likely pathogenic (Variation ID: 16439). Several other probands with a clinical diagnosis of Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (internal lab data, PMID 9338581, 31098894, 31730815, 33059708, 25907466, 19293843, 34916231; PS4). In one individual with aortic dissection and myopia, this variant was reported to be de novo without confirmation of parental relationships (PMID 31098894; 0.25 points). In two families with MFS, this variant was found to segregate with disease in five affected family members (internal lab data; PP1_Strong). This variant is present in in 10/24982 (0.04%) of alleles tested from the Finnish population in gnomAD and did not pass the quality control criteria in the genome subset (PM2_Sup; https://gnomad.broadinstitute.org/ v2.1.1). 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: PVS1_Strong, PS4, PS3, PP1_Strong, PM2_Sup, PP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PS4, PS1, PP4 or PS4, PS1, PP1, PP4 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2022	Functional studies suggest that the variant results in intra-cellular retention of the protein (Jensen et al., 2014); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 96 amino acid residues are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and published literature (HGMD; Lonnqvist et al., 1998; Ritty et al., 1999; Jensen et al., 2014); This variant is associated with the following publications: (PMID: 9817919, 10085138, 11826022, 24982166, 7911051, 10756346, 19293843, 33059708, 33824467, 31098894, 9338581, 31730815, 34008892) -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2022

The p.R2776* pathogenic mutation (also known as c.8326C>T), located in coding exon 65 of the FBN1 gene, results from a C to T substitution at nucleotide position 8326. This changes the amino acid from an arginine to a stop codon within coding exon 65. This alteration occurs at the 3' terminus of theFBN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 96 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration, which is also known as p.R1878*, c.5632C>T, has been reported in multiple individuals with Marfan syndrome (Hayward C et al. Hum. Mutat., 1994;3:159-62; Körkkö J et al. J. Med. Genet., 2002 Jan;39:34-41; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Jensen SA et al. Proc Natl Acad Sci U S A, 2014 Jul;111:10155-60; Proost D et al. Hum Mutat, 2015 Aug;36:808-14; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164; Stengl R et al. Orphanet J Rare Dis, 2020 10;15:290). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Isolated thoracic aortic aneurysm Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Vascular Biology, Beijing Anzhen Hospital

Sep 01, 2018

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 26, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FBN1 protein in which other variant(s) (p.Leu2854Profs*9, p.Gln2830*, p.Leu2854Profs*9) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 16439). This premature translational stop signal has been observed in individual(s) with FBN-1 related conditions (PMID: 7911051, 9338581, 11826022). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg2776*) in the FBN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 96 amino acid(s) of the FBN1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	50
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.85
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137854466; hg19: chr15-48703477; COSMIC: COSV57312804;