rs1555398835

Variant names:

• chr15-48490073-G-A
• rs1555398835
• NM_000138.5:c.2860C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.2860C>T​(p.Arg954Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R954L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 9.99
• Publications: 2 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 19 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 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 chr15-48490072-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1029664.
• 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, 0.95
• PP5: Variant 15-48490073-G-A is Pathogenic according to our data. Variant chr15-48490073-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495582.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.2860C>T	p.Arg954Cys	missense_variant	Exon 25 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.2860C>T	p.Arg954Cys	missense_variant	Exon 24 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.2860C>T	p.Arg954Cys	missense_variant	Exon 25 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111968

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FBN1: PP1:Strong, PM2, PS4:Moderate, PP4 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBN1 c.2860C>T; p.Arg954Cys variant is reported in the literature in patients with Marfan syndrome and Marfan-related disorders (Comeglio 2007, Deng 2008, Hung 2009, Stheneur 2009) and is reported on the FBN1 Universal Mutation Database (UMD). This variant is absent from the general population (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in a highly conserved residue in one of the TGF-beta binding (TB) domains (Yuan 1997), and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. TB domains contain eight conserved cysteine residues and the disulfide bridges formed between these residues are essential for protein folding; addition of a cysteine may interfere with proper disulfide bridge formation, disrupting protein structure. Accordingly, the revised Ghent nosology for Marfan syndrome lists the introduction of cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Based on the above information, this variant is considered pathogenic. References: UMD: http://www.umd.be/FBN1/ Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Deng T et al. Late-onset bilateral lens dislocation and glaucoma associated with a novel mutation in FBN1. Mol Vis. 2008 Jun 30;14:1229-33. Hung C et al. Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. Ann Hum Genet. 2009 Nov;73(Pt 6):559-67. Loeys B et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;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. Yuan X et al. Solution structure of the transforming growth factor beta-binding protein-like module, a domain associated with matrix fibrils. EMBO J. 1997 Nov 17;16(22):6659-66. -

Jan 04, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 32679894, 32209317, 31730815, 29543232, 19328768, 21332468, 19012347, 21883168, 19293843, 18615205, 19839986, 17657824, 19002209, 25907466) -

Marfan syndrome Pathogenic:4 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Likely pathogenic and reported on 07-16-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Sep 19, 2022

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg954Cys variant in the FBN1 gene has been previously reported in at least 6 individuals who fulfilled the diagnostic criteria for Marfan syndrome (Radonic et al., 2011; Sheikhzadeh et al., 2012; Proost et al., 2015; Mannucci et al., 2020), as well as in individuals with ectopia lentis (Chen et al., 2022) and individuals with aortic dissection (Zhao et al., 2020). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 495582). This variant creates a cysteine residue and is located in an established functional domain of the fibrillin1 protein known as the TGF-beta binding domain. Other pathogenic/likely pathogenic variants have been described in this domain (Robinson et al., 2006). The arginine at position 954 is strongly evolutionarily conserved. Computational tools predict that the p.Arg954Cys variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg954Cys variant as pathogenic for autosomal dominant Marfan syndrome based on the information above. [ACMG evidence codes used: PS4; PM1; PM2; PP3] -

Jul 11, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2860C>T (p.Arg954Cys) variant of the FBN1 gene has been observed in multiple individuals (>10) from Marfan syndrome (MFS) cohorts or cohorts with Marfan-related disorders (PMID: 25907466, 21883168, 21332468, 29543232, 19002209, 17657824). This variant has also been reported to segregate in a family with 4 affected individuals having isolated late onset ectopia lentis and three young (<37yo) unaffected family members, suggesting incomplete penetrance (PMID: 18615205). This variant is a cysteine creating variant located in a highly conserved residue in one of the TGF-beta binding (TB) domains. TB domains contain eight conserved cysteine residues and the disulfide bridges formed between these residues are essential for protein folding; addition of a cysteine may interfere with proper disulfide bridge formation, disrupting protein structure (PMID: 20591885). In silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.935). This variant is absent in the general population database gnomAD and interpreted as likely pathogenic /pathogenic by several submitters in ClinVar database (ClinVar ID: 495582). Another amino acid substitutions at the same position (p.Arg954His, p.Arg954Pro) have been classified as likely pathogenic/pathogenic by multiple ClinVar submitters (ClinVar ID: 200005, 961251). Therefore, the c.2860C>T (p.Arg954Cys) variant in FBN1 is classified as pathogenic. -

Apr 10, 2023

deCODE genetics, Amgen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Applied ACMG criteria: PM2, PP2, PP3, PP4, PP5_strong -

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PM7, PP1, PP4 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

May 30, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R954C pathogenic mutation (also known as c.2860C>T), located in coding exon 24 of the FBN1 gene, results from a C to T substitution at nucleotide position 2860. The arginine at codon 954 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in individual(s) with features consistent with Marfan syndrome (Deng T et al. Mol Vis. 2008;14:1229-33; Faivre L et al. Eur J Hum Genet. 2009; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Proost D et al. Hum Mutat. 2015;36:808-14; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164; Chen Z et al. Br J Ophthalmol, 2022 Dec;106:1655-1661). Based on internal structural analysis, the p.R954C variant is anticipated to disrupt a region of known function (Lee SS et al. Structure. 2004 Apr;12(4):717-29). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Dec 28, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The FBN1 c.2860C>T (p.Arg954Cys) variant involves the alteration of a conserved nucleotide and is located in TB domain, which contains eight cysteine residues that form four disulfide bonds. This variant adds a new cysteine residue, which might destroy the disulfide bond formation and further influence the structure and function of FBN1 protein. 4/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 116216 control chromosomes including the large and broad populations from ExAC. In literature, this variant has been reported in several patients (at least 13) who have Marfan or Marfanoid Syndrome. In a family, this variant was found to co-segregate with late onset isolated Ectopia Lentis (Deng_2008). The authors discuss that non-conserved arginine to cysteine substitution is highly related to predominant EL regardless of their location. While in one reported Ghent-positive MFS patient, EL was noted (Faivre_2008), information regarding presence or absence of EL has not been provided in other Ghent positive patients. It has also discussed that patients with EL and a FBN1 mutation are to be categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection (Chandra_2015) and this variant meets this criteria. This variant is also found in patients that do not have isolated EL but atypical/incomplete MFS (Comeglio_2007, Radonic_2011, Sheikhzadeh_2012). Thus, this variant can lead to clinical variability and expressivity of Marfan syndrome. Based on the evidences available, this variant is classified as Pathogenic. -

FBN1-related disorder Pathogenic:1

Nov 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FBN1 c.2860C>T variant is predicted to result in the amino acid substitution p.Arg954Cys. This variant has been reported in multiple individuals with Marfan syndrome (see for example - Comeglio et al. 2007. PubMed ID: 17657824; Stheneur et al. 2009. PubMed ID: 19293843; Hung et al. 2009. PubMed ID: 19839986). This variant was shown to segregate with ectopia lentis in one family (Deng et al. 2008. PubMed ID: 18615205). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Sep 18, 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 954 of the FBN1 protein (p.Arg954Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ectopia lentis and this condition and with Marfan syndrome (PMID: 18615205, 19002209, 19293843, 19839986). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495582). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	34
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.98	D
PhyloP100		10
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.94
MutPred		0.74		Gain of catalytic residue at L955 (P = 0.009);
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		5.7
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555398835; hg19: chr15-48782270; COSMIC: COSV57309410;