rs137854476

chr15-48513552-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.1585C>T(p.Arg529Ter) 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 (★★). 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:10
• Conservation: PhyloP100: 0.550

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 15-48513552-G-A is Pathogenic according to our data. Variant chr15-48513552-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48513552-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.1585C>T	p.Arg529Ter	stop_gained	13/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1585C>T	p.Arg529Ter	stop_gained	12/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1585C>T	p.Arg529Ter	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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PVS1, PP1-M, PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 17, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 2021	The p.R529* pathogenic mutation (also known as c.1585C>T), located in coding exon 12 of the FBN1 gene, results from a C to T substitution at nucleotide position 1585. This changes the amino acid from an arginine to a stop codon within coding exon 12. This alteration has been reported in several individuals with a clinical or suspected diagnosis of Marfan syndrome (Montgomery RA et al. Am. J. Hum. Genet., 1998 Dec;63:1703-11; Rand-Hendriksen S et al. Am J Med Genet A, 2007 Sep;143A:1968-77; Ma M et al. Mol Med Rep, 2016 Jul;14:151-8;Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164). 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

Jun 11, 2019

The FBN1 c.1585C>T; p.Arg529Ter variant (rs137854476) has been reported multiple times in the literature in individuals with Marfan syndrome (Hung 2009, Montgomery 1998, Rand-Hendriksen 2007, Soylen 2009, Stheneur 2009, Tjeldhorn 2006). It is reported as pathogenic in the ClinVar database (Variation ID: 16452), and is absent from general population databases (1000 Genome Project, Exome Variant Server, Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg529Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/16452/ 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. Montgomery RA et al. Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. Am J Hum Genet. 1998 Dec;63(6):1703-11. Rand-Hendriksen S et al. Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome. Am J Med Genet A. 2007 Sep 1;143A(17):1968-77. Soylen B et al. Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations. Clin Genet. 2009 Mar;75(3):265-70. 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. Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006 Winter;10(4):258-64. -

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

May 24, 2016

Variant summary: The FBN1 c.1585C>T (p.Arg529X) variant causes a nonsense mutation resulting in a premature termination codon, which is a commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications, In addition, a reputable database and clinical laboratory have cited the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2023

Not observed in large population cohorts (gnomAD); Published functional study demonstrates near absence of immunohistochemical staining of fibrillin-1 in cultured fibroblasts associated with the R529X variant (Montgomery et al., 1998); 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: 25525159, 31098894, 19159394, 31730815, 27582083, 27175573, 9837823, 27611364, 21907952, 19839986, 19293843, 17663468, 31825148, 32854191, 34498425, 35058154, 30087447) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16452). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 9837823, 17663468, 27175573). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg529*) 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	0.60
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A
Vest4		0.93
GERP RS		3.7

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: rs137854476; hg19: chr15-48805749;