rs1555394195

Positions:

• chr15-48421601-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.7656C>A​(p.Cys2552*) 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: 33)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.21

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: 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 15-48421601-G-T is Pathogenic according to our data. Variant chr15-48421601-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 439701.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.7656C>A	p.Cys2552*	stop_gained	62/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.7656C>A	p.Cys2552*	stop_gained	61/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.7656C>A	p.Cys2552*	stop_gained	62/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	This variant changes 1 nucleotide in exon 62 of the FBN1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with familial thoracic aortic aneurysm and dissection (PMID: 26621581) and in another individual affected with Marfan syndrome (PMID: 35943490). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of FBN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 23, 2018	The p.Cys2552X variant in FBN1 has been reported in 1 individual with clinical f eatures of Marfan syndrome (Regalado 2016) and was absent from large population studies. This variant has been reported in ClinVar by other clinical laboratorie s (Variation ID: 439701). This nonsense variant leads to a premature termination codon at position 2552, which is predicted to lead to a truncated or absent pro tein. Heterozygous loss of function of the FBN1 gene is an established disease m echanism in individuals with Marfan syndrome. In summary, this variant meets cri teria to be classified as pathogenic for Marfan syndrome in an autosomal dominan t manner based upon the predicted impact to the protein, presence in an affected individual, and absence from controls. ACMG/AMP Criteria applied (Richards 2015 ): PVS1; PM2; PS4_Supporting. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2018

The p.C2552* pathogenic mutation (also known as c.7656C>A), located in coding exon 61 of the FBN1 gene, results from a C to A substitution at nucleotide position 7656. This changes the amino acid from a cysteine to a stop codon within coding exon 61. This alteration was detected in a proband reported to have type A aortic dissection, and family history of aortic dissection (Regalado ES et al. Clin. Genet., 2016 Jun;89:719-23). 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. -

Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Jan 20, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.96
GERP RS		3.8

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: rs1555394195; hg19: chr15-48713798;