rs765387131

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP4PP2PP3PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.5518C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 1840 (p.Arg1840Cys) within a calcium binding EGF-like domain of the protein. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure and this variant may impact disulfide bonding (PM1). This variant was found in a proband who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (PMID 31149040, PP4). This variant has been reported three times in ClinVar: twice as likely pathogenic and once as uncertain significance (Variation ID: 519783). It has been reported in the literature in individuals with clinical features of Marfan syndrome (PMID 25652356, 29357934, 37042257, Internal data, PS4_Sup). This variant is present in 1/35435 (0.003%) of alleles tested from the Admixed American population gnomAD (https://gnomad.broadinstitute.org/v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.78, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_Sup, PP2, PP3, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA055122/MONDO:0007947/022

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:8U:2

Conservation

PhyloP100: 2.59

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.5518C>T	p.Arg1840Cys	missense_variant	Exon 45 of 66	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.5518C>T	p.Arg1840Cys	missense_variant	Exon 44 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.5518C>T	p.Arg1840Cys	missense_variant	Exon 45 of 66	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251262

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:3

Sep 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 1840 in a calcium-binding EGF-like domain of the FBN1 protein. Cysteine-creating variants in cbEGF-like domains have been shown to affect protein stability and are overrepresented among patients with Marfan syndrome (PMID: 15161917, 16571647, 17701892). Computational prediction also suggests that this variant may have deleterious impact on protein structure and function. This variant has been reported in an individual affected with Marfan syndrome (PMID: 31149040) and in two unrelated individuals suspected of having Marfan syndrome (PMID: 25652356, 29357934). This variant has been identified in 4/282656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have rarely been reported (PMID: 27274304; 31950671). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v4: 7 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4: 11 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calcium binding EGF domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by an expert panel in ClinVar and reported in the literature in individuals with clinical features of Marfan syndrome (PMID: 25652356, PMID: 29357934, PMID: 31149040, PMID: 37042257). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 22, 2024

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_00138 c.5518C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 1840 (p.Arg1840Cys) within a calcium binding EGF-like domain of the protein. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure and this variant may impact disulfide bonding (PM1). This variant was found in a proband who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (PMID 31149040, PP4). This variant has been reported three times in ClinVar: twice as likely pathogenic and once as uncertain significance (Variation ID: 519783). It has been reported in the literature in individuals with clinical features of Marfan syndrome (PMID 25652356, 29357934, 37042257, Internal data, PS4_Sup). This variant is present in 1/35435 (0.003%) of alleles tested from the Admixed American population gnomAD (https://gnomad.broadinstitute.org/v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.78, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_Sup, PP2, PP3, PP4 -

not provided

Pathogenic:3

Mar 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBN1 c.5518C>T; p.Arg1840Cys variant (rs1161109360) is reported in the literature in one individual who was suspected of Marfan syndrome and one individual with spontaneous coronary artery dissection (Baudhuin 2015, Becerra-Munoz 2018). This variant is also reported in ClinVar (Variation ID: 519783). This variant is only observed on four alleles in the Genome Aggregation Database (v2.1.1), 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 contains six highly-conserved cysteines and the disulfide bridges formed between these residues are essential for protein folding; creation of a novel cysteine may interfere with proper disulfide bridge formation, disrupting protein structure. Accordingly, the revised Ghent nosology for Marfan syndrome lists creation of a cysteine residue as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Computational analyses predict that this variant is deleterious (REVEL: 0.78). Based on available information, this variant is considered to be likely pathogenic. References: Baudhuin LM et al. Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants. J Hum Genet. 2015 May;60(5):241-52. PMID: 25652356. Becerra-MuÃ±oz VM et al. The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. Orphanet J Rare Dis. 2018 Jan 22;13(1):16. PMID: 29357934. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. PMID: 20591885. Wu YS et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem Biol. 1995 Feb;2(2):91-7. PMID: 9383409. -

Dec 19, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Introduces a new cysteine residue within an 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 EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); 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: 29357934, 25652356, 12938084, 31149040, 37042257) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thoracic aortic aneurysm or dissection

Pathogenic:1

Nov 11, 2024

NHS Central & South Genomic Laboratory Hub

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Feb 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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 1840 of the FBN1 protein (p.Arg1840Cys). This variant is present in population databases (rs765387131, gnomAD 0.008%). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 25652356, 29357934). ClinVar contains an entry for this variant (Variation ID: 519783). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Jun 26, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.5518C>T (p.Arg1840Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251262 control chromosomes (gnomAD). c.5518C>T has been reported in the literature in individuals affected with features of Marfan Syndrome (Baudhin_2015, Becerra-Munoz_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25652356, 29357934). ClinVar contains an entry for this variant (Variation ID: 519783). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Jul 13, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1840C variant (also known as c.5518C>T), located in coding exon 44 of the FBN1 gene, results from a C to T substitution at nucleotide position 5518. The arginine at codon 1840 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was described in an individual with some clinical features of Marfan syndrome, but did not fulfill Ghent nosology (Baudhuin LM et al. J. Hum. Genet., 2015 May;60:241-52). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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). However, since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. Family studies may help to elucidate the clinical impact of this alteration. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.74

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Vest4

0.92

MutPred

0.73

Loss of disorder (P = 0.0877);

MVP

0.90

MPC

1.6

ClinPred

1.0

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over