rs730880099

Positions:

• chr15-48510125-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.1633C>T​(p.Arg545Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R545H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 8.12

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 19 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48510124-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 684577.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 15-48510125-G-A is Pathogenic according to our data. Variant chr15-48510125-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 180352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48510125-G-A is described in Lovd as [Pathogenic]. Variant chr15-48510125-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.1633C>T	p.Arg545Cys	missense_variant	14/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1633C>T	p.Arg545Cys	missense_variant	13/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1633C>T	p.Arg545Cys	missense_variant	14/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461080 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726854

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:3

Likely 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	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 13, 2018	The c.1633C>T (p.Arg545Cys) variant in the FBN1 gene has been reported in multiple patients and segregated in two unrelated families with Marfan syndrome (PMID: 9338581, 11700157, 17657824, 19159394, 25944730, 27353645). The variant is not observed in the gnomAD. Therefore, this c.1633C>T (p.Arg545Cys) variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 06, 2015	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 09, 2021	This missense variant replaces arginine with cysteine at codon 545 in an epidermal-growth-factor (EGF)-like domain of the FBN1 protein. Although functional studies have not been reported, this variant generates a cysteine residue in an important functional domain and is likely to affect protein structure and stability (PMID: 4750422, 16677079). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in multiple individuals affected with Marfan syndrome, ectopia lentis or aortopathy (PMID: 12446365, 15241795, 17679947, 19159394, 20564469, 27611364, 27353645). This variant has been reported to segregate with aortic dissection and ectopia lentis in ten individuals from a family affected with Marfan syndrome (PMID: 27353645). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2022	The p.R545C pathogenic mutation (also known as c.1633C>T), located in coding exon 13 of the FBN1 gene, results from a C to T substitution at nucleotide position 1633. The arginine at codon 545 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #04 domain. 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 alteration has been described in several patients with ectopia lentis and Marfan syndrome (Loeys B et al. Arch Intern Med. 2001;161(20):2447-54; Jin C et al. Mol Vis. 2007;13:1280-4, Comeglio P et al. Hum Mutat. 2007;28(9):928). Additionally, this alteration was observed to co-segregate in multiple relatives in two unrelated multi-generation families (Hayward C et al. Hum Mutat. 1997;10(4):280-9; Li Y et al. Clin. Chim. Acta, 2016 Sep;460:102-6). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, p.R545C is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 17, 2021	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 23, 2017

- -

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

Oct 10, 2016

Variant summary: The FBN1 c.1633C>T (p.Arg545Cys) variant involves the alteration of a highly conserved nucleotide and is located in the Ca2+-binding EGF-like #4 domain with 5/5 in silico tools predicting a deleterious outcome. This change disrupts disulfide bonds 541-555 (C4) which affects the secondary or tertiary structure and possibly impairing fibrillin interactions. The variant is absent from control dataset of ExAC and but has been reported in numerous affected individuals predominantly with isolated EL via published reports, although several pts with classical MFS have also been reported, including within families presenting with EL. Two published reports clearly indicate segregation of the variant with the disease (Hayward, 1997 and Li, 2016). The variant has been cited by several reputable databases/clinical laboratories as Pathogenic. Taking together, the variant was classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 04, 2021

Not observed at significant frequency in large population cohorts (Lek et al., 2016); Introduces a new 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID#180352; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 11700157, 20021881, 20564469, 12446365, 27611364, 22772377, 28642162, 25053872, 31447099, 32123317, 12938084, 19159394, 27353645, 9338581, 17679947) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 09, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 545 of the FBN1 protein (p.Arg545Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ectopia lentis and/or Marfan syndrome (PMID: 9338581, 12446365, 15241795, 17679947, 19159394, 20564469, 27353645, 27611364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180352). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Ectopia lentis 1, isolated, autosomal dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Suma Genomics

-

- -

Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.88
MutPred		0.80		Loss of disorder (P = 0.133);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.5

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: rs730880099; hg19: chr15-48802322; COSMIC: COSV57313786;