chr15-48472665-A-G

Position:

• chr15-48472665-A-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.4222T>C​(p.Cys1408Arg) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 9.32

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 17 ACMG points.

• PM1: In a disulfide_bond (size 12) in uniprot entity FBN1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000138.5
• 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, 0.996
• PP5: Variant 15-48472665-A-G is Pathogenic according to our data. Variant chr15-48472665-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 42351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48472665-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.4222T>C	p.Cys1408Arg	missense_variant	35/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4222T>C	p.Cys1408Arg	missense_variant	34/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4222T>C	p.Cys1408Arg	missense_variant	35/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PVS2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 18, 2014	The Cys1408Arg variant in FBN1 has been previously reported in 4 individuals wit h clinical features of Marfan syndrome, segregated with disease in 5 affected fa mily members from 1 family including 2 obligate carriers, and was absent from la rge population studies (Stheneur 2009, Yoo 2010, LMM unpublished data). The cyst eine (Cys) at position 1408 is highly conserved in mammals and evolutionarily di stant species, supporting that a change at this position may not be tolerated. I n addition, this variant affects a cysteine residue; cysteine substitutions are a common finding in individuals with Marfan syndrome (Schrijver, 1999). In summa ry, this variant meets our criteria to be classified as pathogenic based on the available evidence described above (http://pcpgm.partners.org/LMM). -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2021

The p.C1408R pathogenic mutation (also known as c.4222T>C), located in coding exon 34 of the FBN1 gene, results from a T to C substitution at nucleotide position 4222. The cysteine at codon 1408 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in association with Marfan syndrome and thoracic aortic aneurysm and dissection (TAAD) (Tan L et al. Hum Mol Genet, 2017 12;26:4814-4822; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Baetens M et al. Hum Mutat, 2011 Sep;32:1053-62; Lerner-Ellis JP et al. Mol Genet Metab, 2014 Jun;112:171-6; Gentilini D et al. PLoS One, 2019 Sep;14:e0222506; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, other alterations affecting the same amino acid, p.C1408F (c.4223G>T) and p.C1408S (c.4223G>C), have been reported in association with FBN1-related disease (Tiecke F et al. Eur J Hum Genet, 2001 Jan;9:13-21; Tan L et al. Hum Mol Genet, 2017 12;26:4814-4822). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive EGF/cbEGF domain #20. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2019

Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1 related disorders (Collod-Beroud et al., 2003).; Reported in ClinVar as pathogenic and reported by one external lab to segregate with disease in multiple affected relatives from one family (ClinVar Variant ID# 42351; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31536524, 19293843, 19863550, 24793577, 31730815) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2022

For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). 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: 42351). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1408 of the FBN1 protein (p.Cys1408Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 19293843, 19863550). In at least one individual the variant was observed to be de novo. -

Stiff skin syndrome;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4707243:Familial thoracic aortic aneurysm and aortic dissection Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 05-02-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.98	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		1.0
MutPred		0.98		Gain of disorder (P = 0.0516);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8

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: rs397515802; hg19: chr15-48764862;