rs140583

Positions:

• chr15-48495219-G-A

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.2581C>T​(p.Arg861Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.30

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 15-48495219-G-A is Pathogenic according to our data. Variant chr15-48495219-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.2581C>T	p.Arg861Ter	stop_gained	22/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.2581C>T	p.Arg861Ter	stop_gained	21/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.2581C>T	p.Arg861Ter	stop_gained	22/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

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 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, no assertion criteria provided	research	Centre for Genomic and Experimental Medicine, University of Edinburgh	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 29, 2018	The p.R861* pathogenic mutation (also known as c.2581C>T), located in coding exon 21 of the FBN1 gene, results from a C to T substitution at nucleotide position 2581. This changes the amino acid from an arginine to a stop codon within coding exon 21. This alteration has been reported in multiple individuals with Marfan syndrome (MFS) or MFS-related phenotypes (Liu WO et al. Genet Test. 1997-1998;1(4):237-42; Schrijver I et al. Am J Hum Genet. 2002;71(2):223-37; Arbustini E et al. Hum Mutat. 2005;26(5):494; Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8; Katzke S et al. Hum Mutat 2002; 20(3):197-208; Magyar I et al. Hum Mutat. 2009;30(9):1355-64; Guo J et al. Sci Rep. 2015;5:13115). One study of patient-derived induced pluripotent stem cells exhibiting this mutation reported impact to microfibril formation, osteogenesis, contractility, and calcium influx, with rescue of some defects in mutation-corrected cells (Park JW et al. Int J Biol Sci. 2017;13(5):588-603). 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 specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 25, 2016

- -

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/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

Mar 20, 2017

Variant summary: The FBN1 c.2581C>T (p.Arg861X) variant results in a premature termination codon, predicted to cause a truncated or absent FBN1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 121196 control chromosomes (ExAC). Multiple publications cite the variant in affected individuals, along with multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 2021

Not observed in large population cohorts (Lek et al., 2016); 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 using induced pluripotent stem cells demonstrated that this variant decreases FBN1 protein expression, impairs osteogenesis, reduces contractility and alters calcium signaling in derivative mesenchymal stem cells and/or vascular smooth muscle cells (Park et al., 2017); Reported in ClinVar as pathogenic (ClinVar Variant ID# 265401; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 26272055, 29357934, 29543232, 10464652, 12203992, 12068374, 19293843, 22005308, 19618372, 19533785, 16222657, 17657824, 28539832) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg861*) 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 premature translational stop signal has been observed in individual(s) with Marfan syndrome, clinical features consistent with Marfan syndrome, or thoracic aortic aneurysm and dissection and Marfan syndrome (PMID: 2005308, 10464652, 16222657, 17657824, 19293843, 26272055). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265401). For these reasons, this variant has been classified as Pathogenic. -

Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Nov 19, 2021

FBN1 NM_000138.4 exon 22 p.Arg861* (c.2581C>T): This variant has been reported in the literature in several individuals with features or a clinical diagnosis of Marfan syndrome, including at least 1 individual as de novo (Katzke 2002 PMID:12203992, Schrijver 2002 PMID:12068374, Arbustini 2005 PMID:16222657, Comeglio 2007 PMID:17657824, Chung 2009 PMID:19533785, Magyar 2009 PMID:19618372, Stheneur 2009 PMID:19293843, Guo 2015 PMID:26272055). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:265401). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Dietz 2017 PMID: 20301510). In summary, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A
Vest4		0.98
GERP RS		4.6

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: rs140583; hg19: chr15-48787416; COSMIC: COSV57319926;