rs137854467

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_000138.5(FBN1):c.364C>T(p.Arg122Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R122H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 4.61

Publications

16 publications found

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 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)

FBN1 links:

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ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 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, 0.933

PP5

Variant 15-48600217-G-A is Pathogenic according to our data. Variant chr15-48600217-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16440.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 link	c.364C>T	p.Arg122Cys	missense_variant	Exon 5 of 66	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.364C>T	p.Arg122Cys	missense_variant	Exon 4 of 65		NP_001393645.1
FBN1	NM_001406717.1 link	c.364C>T	p.Arg122Cys	missense_variant	Exon 5 of 9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN1	ENST00000316623.10 link	c.364C>T	p.Arg122Cys	missense_variant	Exon 5 of 66	1	NM_000138.5	ENSP00000325527.5	P35555
FBN1	ENST00000559133.6 link	n.364C>T		non_coding_transcript_exon_variant	Exon 5 of 67	1		ENSP00000453958.2	H0YND0
FBN1	ENST00000537463.6 link	n.364C>T		non_coding_transcript_exon_variant	Exon 5 of 31	5		ENSP00000440294.2	F6U495
FBN1	ENST00000674301.2 link	n.364C>T		non_coding_transcript_exon_variant	Exon 5 of 68			ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jan 18, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); Reported in ClinVar by several laboratories as pathogenic (ClinVar Variant ID# 16440); This variant is associated with the following publications: (PMID: 19293843, 25053872, 22772377, 19839986, 12446365, 21932315, 21895641, 11700157, 19089573, 17679947, 9452085, 24161884, 24199744, 32123317, 8040326, 34957211, 12938084, 31730815) -

Jul 20, 2018

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Marfan syndrome

Pathogenic:3

Aug 18, 2011

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

- -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 04, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.60; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016440 /PMID: 8040326). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 21895641, 21932315, 22772377). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:2

Jul 28, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R122C pathogenic mutation (also known as c.364C>T), located in coding exon 4 of the FBN1 gene, results from a C to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the EGF-like #02 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 particular alteration has been detected in numerous unrelated individuals with ectopia lentis (EL) and/or Marfan syndrome (MFS) (e.g., Loeys B et al. Arch. Intern. Med. 2001;161:2447-54; Comeglio P et al. Br J Ophthalmol. 2002;86:1359-62; Jin C et al. Mol. Vis. 2007;13:1280-4; Hung CC et al. Ann. Hum. Genet. 2009;73:559-67; Li J et al. Mol. Vis. 2014;20:1017-24). In addition, this alteration has been reported to segregate with disease in three families (Ståhl-Hallengren C et al. J. Clin. Invest. 1994;94:709-13; Black C et al. Hum. Mutat. 1998;Suppl 1:S198-200; Zadeh N et al. Am. J. Med. Genet. A. 2011;155A:2661-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

May 17, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Pathogenic:1

Aug 13, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FBN1 c.364C>T; p.Arg122Cys variant (rs137854467) has been reported in multiple families with clinical symptoms suggestive of Marfan syndrome, and is strongly associated with ectopia lentis (Black 1998, Comeglio 2002, Jin 2007, Loeys 2001, Stahl-Hallengran 1994). It is reported in ClinVar as pathogenic (Variation ID: 16440) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The variant changes an arginine in an EGF-like domain into a cysteine residue, which meets the revised Ghent nosology criteria of a causative Marfan syndrome variant (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Black C et al. Correlation of a recurrent FBN1 mutation (R122C) with an atypical familial Marfan syndrome phenotype. Hum Mutat. 1998; Suppl 1:S198-200. Comeglio P et al. Identification of FBN1 gene mutations in patients with ectopia lentis and marfanoid habitus. Br J Ophthalmol. 2002; 86(12):1359-62. Jin C et al. Novel FBN1 mutations associated with predominant ectopia lentis and marfanoid habitus in Chinese patients. Mol Vis. 2007; 13:1280-4. Loeys B et al. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001; 2001 Nov 12;161(20):2447-54. Loeys B et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010; 47(7):476-85. Stahl-Hallengren C et al. An extra cysteine in one of the non-calcium-binding epidermal growth factor-like motifs of the FBN1 polypeptide is connected to a novel variant of Marfan syndrome. J Clin Invest. 1994; 94(2):709-13. -

Marfan syndrome, atypical

Pathogenic:1

Aug 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Arachnodactyly;C0023316:Lens subluxation;C0240635:High palate;C0340643:Aortic dissection

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Jan 13, 2025

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 122 of the FBN1 protein (p.Arg122Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ectopia lentis and/or Marfan syndrome (PMID: 8040326, 9452085, 11700157, 12446365, 17679947, 21895641, 21932315, 22772377, 25053872). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16440). 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. -

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

Aug 23, 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

0.88

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.44

PhyloP100

4.6

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.60

Sift

Benign

0.034

Sift4G

Benign

0.10

Vest4

0.88

MutPred

0.76

Loss of solvent accessibility (P = 0.4011);

MVP

0.92

MPC

1.7

ClinPred

0.98

GERP RS

6.2

Mutation Taster

=41/59

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over