chr15-48489896-C-T

Position:

• chr15-48489896-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.3037G>A​(p.Gly1013Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 U:1
• Conservation: PhyloP100: 7.90

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 15-48489896-C-T is Pathogenic according to our data. Variant chr15-48489896-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48489896-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-48489896-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3037G>A	p.Gly1013Arg	missense_variant	25/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3037G>A	p.Gly1013Arg	missense_variant	24/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3037G>A	p.Gly1013Arg	missense_variant	25/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:7 Uncertain:1

Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 11, 2016	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.3037G>A;p.(Gly1013Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 177648; PMID: 21784848; 19002209; 16220557; 14695540; 11780406) - PS4.Same amino acid change as a previously established Pathogenic variant regardless of nucleotide change (ClinVar ID: 16455; PMID: 11175294) - PS1.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21784848) - PS3_moderate. This variant is not present in population databases:rs140593, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Feb 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a heterozygous change in patients with Marfan syndrome (PMID: 7611299, 11175294, 14695540, 10464652, 11700157, 11780406, 16220557, 19002209). It falls in a hotspot for a severe early onset cardiovascular phenotype and has been reported in unrelated patients with atypically severe manifestations (PMID: 7611299, 32198975). Experimental studies have shown that this variant affects the FBN1 protein by inducing the loss of heparin binding and enhancing the susceptibility to proteolysis (PMID: 21784848). It is absent from the gnomAD population database and thus is presumed to be rare. The c.3037G>A (p.Gly1013Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3037G>A (p.Gly1013Arg) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 26, 2022	ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated, PP2 supporting, PP3 supporting -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2023	Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14695540, 27437668, 34550612, 31061752, 33436942, 32198975, 7611299, 11175294, 10464652, 11700157, 16220557, 19002209, 22772377, 11780406, no PMID, 17701892, 10930463, 33495528, 21135753, 32679894, 29939511, 35058154, 12938084, 21784848) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Dec 11, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The p.G1013R pathogenic mutation (also known as c.3037G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 3037. The glycine at codon 1013 is replaced by arginine, an amino acid with dissimilar properties, and is located in the TGFBP #03 domain. This alteration has been reported in numerous individuals with a clinical diagnosis of Marfan syndrome, including as a de novo alteration in an individual with neonatal Marfan syndrome with a severe, atypical presentation (Nijbroek G et al. Am J Hum Genet, 1995 Jul;57:8-21; Biggin A et al. Hum Mutat, 2004 Jan;23:99; Ardhanari M et al. J Pediatr Genet, 2019 Jun;8:86-90; Rommel K et al. Hum Mutat, 2005 Dec;26:529-39; Stark VC et al. Genes (Basel), 2020 07;11; Arnaud P et al. Genet Med, 2021 05;23:865-871). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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 11, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 177648). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 7611299, 10464652, 11175294, 11700157, 11780406, 14695540, 16220557, 19002209). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1013 of the FBN1 protein (p.Gly1013Arg). Experimental studies have shown that this missense change affects FBN1 function (PMID: 21784848). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.065	T
Vest4		1.0
MutPred		0.72		Loss of ubiquitination at K1017 (P = 0.0821);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.6

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: rs140593; hg19: chr15-48782093;