rs25403

Variant names:

• chr15-48613073-G-A
• rs25403
• NM_000138.5:c.184C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-48613073-G-A
• chr15-48613073-G-C

Variant summary

Our verdict is Pathogenic. The variant received 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. 11/19 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. R62H) has been classified as Uncertain significance.

• 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
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to Marfan syndrome, Weill-Marchesani syndrome 2, dominant, progeroid and marfanoid aspect-lipodystrophy syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, stiff skin syndrome, familial thoracic aortic aneurysm and aortic dissection, isolated ectopia lentis, ectopia lentis 1, isolated, autosomal dominant, Acromicric dysplasia, neonatal Marfan syndrome, Weill-Marchesani 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 VariationId is 42295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.184C>T	p.Arg62Cys	missense_variant	Exon 3 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.184C>T	p.Arg62Cys	missense_variant	Exon 2 of 65		NP_001393645.1
FBN1	NM_001406717.1	c.184C>T	p.Arg62Cys	missense_variant	Exon 3 of 9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.184C>T	p.Arg62Cys	missense_variant	Exon 3 of 66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.184C>T		non_coding_transcript_exon_variant	Exon 3 of 67	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.184C>T		non_coding_transcript_exon_variant	Exon 3 of 31	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.184C>T		non_coding_transcript_exon_variant	Exon 3 of 68			ENSP00000501333.2

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

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111452

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000127 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Jun 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 21, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Marfan syndrome Pathogenic:3

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Apr 14, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.184C>T (p.R62C) alteration is located in exon 3 (coding exon 2) of the FBN1 gene. This alteration results from a C to T substitution at nucleotide position 184, causing the arginine (R) at amino acid position 62 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in several patients with ectopia lentis and Marfan syndrome; in at least one individual, it was determined to be de novo (Körkkö, 2002; Katzke, 2002). In addition, this variant has been observed to co-segregate in multiple relatives in families with bilateral ectopia lentis (Yu, 2006). This amino acid position is well conserved in available vertebrate species. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Familial ectopia lentis Pathogenic:1

Jan 23, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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 also known as R114C. ClinVar contains an entry for this variant (Variation ID: 42295). 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. -

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

Nov 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		7.0
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
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

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