rs25403

Positions:

• chr15-48613073-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000138.5(FBN1):​c.184C>T​(p.Arg62Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R62H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.00

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 15 ACMG points.

• PM1: In a disulfide_bond (size 9) in uniprot entity FBN1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) 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, 0.924
• PP5: Variant 15-48613073-G-A is Pathogenic according to our data. Variant chr15-48613073-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48613073-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.184C>T	p.Arg62Cys	missense_variant	3/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.184C>T	p.Arg62Cys	missense_variant	2/65		NP_001393645.1
FBN1	NM_001406717.1	c.184C>T	p.Arg62Cys	missense_variant	3/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.184C>T	p.Arg62Cys	missense_variant	3/66	1	NM_000138.5	ENSP00000325527	P1
FBN1	ENST00000559133.6	c.184C>T	p.Arg62Cys	missense_variant, NMD_transcript_variant	3/67	1		ENSP00000453958
FBN1	ENST00000674301.2	c.184C>T	p.Arg62Cys	missense_variant, NMD_transcript_variant	3/68			ENSP00000501333
FBN1	ENST00000537463.6	c.184C>T	p.Arg62Cys	missense_variant, NMD_transcript_variant	3/31	5		ENSP00000440294

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460866 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726760

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000117 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2022	Identified primarily in patients with isolated ectopia lentis (EL) in published literature (Korkko et al., 2002; Katzke et al., 2002; Ades et al., 2004; Yu et al., 2006; Zhao et al., 2013; Wooderchak-Donahue et al., 2015; Stark et al., 2020; Chen et al., 2021; Zhou et al., 2021) and in patients referred for genetic testing at GeneDx; Identified in a patient with bilateral ectopia lentis, aortic dilation, and arachnodactyly (Katze et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine residue within a calcium-binding EGF-like 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 (Collod-Beroud et al., 2003); Arginine (R) to cysteine (C) changes in the FBN1 are suspected to be predominantly associated with isolated EL (Jin et al., 2007); 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: 11826022, 18079676, 15054843, 27611364, 25944730, 16765689, 22950452, 32123317, 12203987, 12203992, 17679947, 32679894, 34281902, 33576469) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 20, 2019	The FBN1 c.184C>T; p.Arg62Cys variant (rs25403), is reported in the literature in multiple individuals with symptoms or a diagnosis of Marfan syndrome or a related aortopathy (Katzke 2002, Korkko 2002, Stheneur 2009, Yang 2009, Zhao 2013). In one family with isolated ectopia lentis, the p.Arg62Cys variant was found to segregate in all affected individuals (Zhao 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant creates a cysteine residue in one of the calcium binding EGF-like domains of fibrillin-1 (Wu 1995). Each EGF-like domain normally contains six highly-conserved cysteines and the disulfide bridges formed between these residues are essential for protein folding; disruption of the normal pattern of cysteines may interfere with proper disulfide bridge formation, disrupting protein structure. Accordingly, the revised Ghent nosology for Marfan syndrome lists missense variants of cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Katzke S et al. TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Hum Mutat. 2002 Sep;20(3):197-208. Korkko J et al. Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. J Med Genet. 2002 Jan;39(1):34-41. Loeys et al. The revised Ghent nosology for the Marfan syndrome. J. Med. Genet. 2010 47(7): 476-85. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Yang H et al. Genetic testing of 248 Chinese aortopathy patients using a panel assay. Sci Rep. 2016 Sep 9;6:33002. Zhao JH et al. Ophthalmic findings in a family with early-onset isolated ectopia lentis and the p.Arg62Cys mutation of the fibrillin-1 gene (FBN1). Ophthalmic Genet. 2013 Mar-Jun;34(1-2):21-6. -

Marfan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
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

Feb 26, 2018

The p.R62C pathogenic mutation (also known as c.184C>T), located in coding exon 2 of the FBN1 gene, results from a C to T substitution at nucleotide position 184. The arginine at codon 62 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the 4-cys motif LTBP-like domain near the cb EGF-like #01 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 reported in several patients with ectopia lentis and Marfan syndrome, and in some cases, inheritance has been described as likely de novo (Körkkö J et al. J Med Genet. 2002;39:34-41; Katzke S et al. Hum Mutat. 2002;20:197-208). Additionally, this alteration has been observed to co-segregate in multiple relatives in families with bilateral ectopia lentis (Yu R et al. Am J Ophthalmol. 2006;141(6):1136-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial ectopia lentis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 23, 2023

Variant summary: FBN1 c.184C>T (p.Arg62Cys) results in a non-conservative amino acid change located in the fibrillin unique N-terminal (FUN) domain (IPR040872) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249372 control chromosomes (gnomAD). The variant, c.184C>T, has been reported in the literature in several individuals, who were mostly affected with Familial Ectopia Lentis, but individuals affected with (suspected) Marfan Syndrome were also described (e.g. Korkko_2002, Katzke_2002, Robinson_2011, Yu_2006, Zhao_2012, Chen_2022); in several families the variant co-segregated with ectopia lentis. These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant might affect TGF-beta1 signaling (Chaudhry_2007). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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 19, 2023

This variant is also known as R114C. This missense change has been observed in individual(s) with ectopia lentis (PMID: 11826022, 12203992, 16765689, 22950452, 25053872, 25944730, 27611364). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 62 of the FBN1 protein (p.Arg62Cys). ClinVar contains an entry for this variant (Variation ID: 42295). For these reasons, this variant has been classified as Pathogenic. 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. -

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

Nov 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.65	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.91
MutPred		0.65		Loss of disorder (P = 0.0899);
MVP		0.93
MPC		1.7
ClinPred		1.0	D
GERP RS		5.1

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: rs25403; hg19: chr15-48905270; COSMIC: COSV57314909;