rs113812345

Positions:

• chr15-48513591-G-A
• chr15-48513591-G-T

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.1546C>T​(p.Arg516Ter) variant causes a stop gained change. 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.71

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48513591-G-A is Pathogenic according to our data. Variant chr15-48513591-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48513591-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.1546C>T	p.Arg516Ter	stop_gained	13/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1546C>T	p.Arg516Ter	stop_gained	12/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1546C>T	p.Arg516Ter	stop_gained	13/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 13, 2020	- -
Pathogenic, 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	PM2, PVS1, PP4 or PM2, PVS1, PP1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 18, 2020	The p.Arg516X variant in FBN1 has been reported in 5 individuals with Marfan Syndrome and segregated with disease in 1 affected individual (Arbustini 2005 PMID: 16222657, Magyar 2009 PMID: 19618372, Baetens 2011 PMID: 21542060, Aalberts 2014 PMID: 24161884, Yang 2016 PMID: 27234404, Li 2019 PMID: 31098894). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 42285). This nonsense variant leads to a premature termination codon at position 516, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an established disease mechanism in Marfan Syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Marfan Syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4. -
Pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Jul 12, 2016	The p.Arg516* variant present in various studies and been reported in ClinVar by other submitters (ClinVar Variation ID:42285). Evaluation in our clinical center was made with in silico method with the use of NetGene2, Provean, SIFT, MutationTaster. All calculations suggest deleterious/damaging effect. Additionally FBN1 know to be intolerant to LoF variants (deletions, frameshifts, stop-gain, etc.) with ExAC pLI=1.00. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 31, 2016

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2021

The p.R516* pathogenic mutation (also known as c.1546C>T) located in coding exon 12 of the FBN1 gene, results from a C to T substitution at nucleotide position 1546. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation has been reported in several individuals with a clinical diagnosis of Marfan syndrome (Arbustini et al. Hum Mutat. 2005 Nov; 26(5): 494; Baetens et al. Hum Mutat. 2011; 32(9):1053-62; Proost D et al. Hum Mutat, 2015 Aug;36:808-14; Stark VC et al. Genes (Basel), 2020 07;11:[Epub ahead of print]). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2023

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; Published functional studies demonstrate no mutant transcript was detected in cycloheximide untreated fibroblasts (Magyar et al., 2009); This variant is associated with the following publications: (PMID: 25525159, 27234404, 19618372, 31098894, 32679894, 34498425, 21542060, 24161884, 25907466, 19293843, 35058154, 16222657, 33174221) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

This sequence change creates a premature translational stop signal (p.Arg516*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Marfan syndrome (PMID: 16222657, 17657824, 19293843, 19618372, 27234404). ClinVar contains an entry for this variant (Variation ID: 42285). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A
Vest4		0.94
GERP RS		4.9

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: rs113812345; hg19: chr15-48805788;