rs200309328

chr15-48412715-G-Achr15-48412715-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000138.5(FBN1):c.8080C>T(p.Arg2694Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R2694R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 1.57

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 65 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48412715-G-A is Pathogenic according to our data. Variant chr15-48412715-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 163461.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.8080C>T	p.Arg2694Ter	stop_gained	65/66	ENST00000316623.10
FBN1	NM_001406716.1	c.8080C>T	p.Arg2694Ter	stop_gained	64/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.8080C>T	p.Arg2694Ter	stop_gained	65/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PVS1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 07, 2014	The Arg2694X variant in FBN1 has been reported in at least 10 individuals with s uspected or confirmed Marfan syndrome (Biggin 2004, Chen 2007, Attanasio 2008, S theneur 2009, Hung 2009). It was absent from large population studies. This non sense variant leads to a premature termination codon at position 2694, which is predicted to lead to a truncated or absent protein. Heterozygous loss of functio n of the FBN1 gene is an established disease mechanism in Marfan syndrome. In su mmary, this variant meets our criteria to be classified as pathogenic (http://pc pgm.partners.org/LMM). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Sep 28, 2023	The NM_00138 c.8080C>T, is a nonsense variant in FBN1 which is predicted to result in a premature stop codon at position 2694, and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with thoracic aortic aneurysm, ectopia lentis, and a systemic score of 10, which is a highly specific phenotype for Marfan syndrome (internal data) (PP4). The variant has been identified as a de novo occurrence, without confirmation of paternity and maternity, in one individual with highly specific phenotype and in one individual with a phenotype consistent with the gene but not highly specific (Internal data- Bichat) (PM6). This variant was also found in a proband with ectopia lentis, thoraic aortic aneurysm, and skeletal features, and was found to segregate with the disease in 1 affected family member (internal data, John Hopkins). This variant has been reported 9 times in ClinVaras pathogenic (Variation ID: 163461). At least 20 other probands with a clinical diagnosis of Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (PMID 17680538, 19293843, 19839986, 24199744, 26787436, 14695540, 18435798, 26133393, internal data, PS4). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). 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, PS4, PM6, PM2_Sup, PP4. -
Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 12, 2018

The FBN1 c.8080C>T; p.Arg2694Ter variant (rs193922108) is reported in the literature in multiple individuals affected with Marfan syndrome (Attanasio 2008, Biggin 2004, Chen 2007, Hung 2009, Stheneur 2009). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 163461). It is found on one chromosome in the Exome Variant Server but is otherwise absent from general population databases (1000 Genomes Project and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Nonsense variants in FBN1 meet the revised Ghent nosology criteria for classification as pathogenic (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Attanasio M et al. FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Clin Genet. 2008 Jul;74(1):39-46. Biggin A et al. Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat. 2004 Jan;23(1):99. Chen XJ et al. Two gene mutations in fibrillin 1 of Marfan syndrome. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007 Aug;24(4):440-2. Hung CC et al. Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. Ann Hum Genet. 2009 Nov;73(Pt 6):559-67. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2022

The p.R2694* pathogenic mutation (also known as c.8080C>T), located in coding exon 64 of the FBN1 gene, results from a C to T substitution at nucleotide position 8080. This changes the amino acid from an arginine to a stop codon within coding exon 64. This variant has been detected in several unrelated individuals with Marfan syndrome (MFS) or features consistent with MFS (Biggin A et al. Hum Mutat, 2004 Jan;23:99; Attanasio M et al. Clin Genet, 2008 Jul;74:39-46; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Hung CC et al. Ann Hum Genet, 2009 Nov;73:559-67; Pees C et al. Clin Genet, 2014 Dec;86:552-7; Franken R et al. Eur Heart J, 2016 Nov;37:3285-3290; Zarate YA et al. Genet Med, 2016 Apr;18:356-63; Wu Y et al. Biosci Rep, 2020 12;40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 16, 2019

Variant summary: FBN1 c.8080C>T (p.Arg2694X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251382 control chromosomes (gnomAD). c.8080C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (Franken_206, Attanasio_2008, Biggin_2004, Hung_2009, Pees_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 04, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22913777, 24941995, 16061422, 19293843, 17680538, 18435798, 14695540, 26787436, 19839986, 25525159, 24199744, 26133393, 31536524) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 163461). This premature translational stop signal has been observed in individual(s) with Marfan syndrome (PMID: 14695540, 17680538, 18435798, 19293843, 19839986, 26787436). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2694*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	A
Vest4		0.92
GERP RS		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200309328; hg19: chr15-48704912; COSMIC: COSV104608696;