rs111687884

Positions:

• chr15-48537704-G-A
• chr15-48537704-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.643C>T​(p.Arg215Ter) 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:9
• Conservation: PhyloP100: 3.55

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 15-48537704-G-A is Pathogenic according to our data. Variant chr15-48537704-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48537704-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.643C>T	p.Arg215Ter	stop_gained	7/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.643C>T	p.Arg215Ter	stop_gained	6/65		NP_001393645.1
FBN1	NM_001406717.1	c.643C>T	p.Arg215Ter	stop_gained	7/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.643C>T	p.Arg215Ter	stop_gained	7/66	1	NM_000138.5	ENSP00000325527	P1
FBN1	ENST00000559133.6	c.643C>T	p.Arg215Ter	stop_gained, NMD_transcript_variant	7/67	1		ENSP00000453958
FBN1	ENST00000674301.2	c.643C>T	p.Arg215Ter	stop_gained, NMD_transcript_variant	7/68			ENSP00000501333
FBN1	ENST00000537463.6	c.636+7C>T		splice_region_variant, intron_variant, NMD_transcript_variant		5		ENSP00000440294

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:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 01, 2011	The Arg215X variant has been reported in the literature in one individual with c linical features of Marfan syndrome (Matsukawa 2001). This variant leads to a pr emature stop codon at position 215, which is predicted to lead to a truncated or absent protein. Therefore, this variant is highly likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Nov 03, 2022	The c.643C>T;p.(Arg215*) variant creates a premature translational stop signal in the FBN1 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 42401; PMID: 11139245; 16220557; 17657824; 27611364; 32431097) - PS4. This variant is not present in population databases (rs111687884, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 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: 25525159, 11139245, 31098894, 29357934, 32431097, 17657824, 19293843, 27234404, 27611364, 16220557, AgaogluNB2022, 15241795) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 23, 2020	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 24, 2017

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2015

The p.R215* pathogenic mutation (also known as c.643C>T), located in coding exon 6 of the FBN1 gene in the hybrid #01 domain, results from a C to T substitution at nucleotide position 643. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation was originally reported in a 57-year-old male Japanese patient with a severe phenotype of ocular, skeletal, and cardiovascular features and positive family history. He had an acute aortic dissection at 38 years of age and also had annulo-aortic ectasia and aortic regurgitation (Matsukawa R et al. Hum Mutat. 2001;17(1):71-2). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

This sequence change creates a premature translational stop signal (p.Arg215*) 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 individuals with Marfan syndrome (PMID: 11139245, 16220557, 17657824, 27611364). ClinVar contains an entry for this variant (Variation ID: 42401). 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	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A
Vest4		0.95
GERP RS		2.3

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: rs111687884; hg19: chr15-48829901;