rs193922228

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000138.5(FBN1):c.6806T>C(p.Ile2269Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,510 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 9.32

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 Pathogenic. Variant got 17 ACMG points.

PM1

In a disulfide_bond (size 16) in uniprot entity FBN1_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) 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, 0.971

PP5

Variant 15-48430736-A-G is Pathogenic according to our data. Variant chr15-48430736-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48430736-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.6806T>C	p.Ile2269Thr	missense_variant	56/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1 linkuse as main transcript	c.6806T>C	p.Ile2269Thr	missense_variant	55/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.6806T>C	p.Ile2269Thr	missense_variant	56/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461320

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727032

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

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:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 26, 2016	The p.Ile2269Thr variant in FBN1 has been reported in 9 individuals with Marfan syndrome or features of Marfan syndrome, including 2 individuals in whom the var iant occurred de novo (Katzke 2002, Comeglio 2007, Attanasio 2008, Stheneur 2009 , Soylen 2009, Proost 2015, LMM unpublished data). This variant was absent from large population studies. Computational prediction tools and conservation analys is suggest that this variant may impact the protein. In summary, the p.Ile2269Th r variant meets our criteria to be classified as pathogenic for Marfan syndrome in an autosomal dominant manner based upon presence in affected individuals, abs ence from controls and de novo occurrences. -
Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2018	The c.6806T>C; p.Ile2269Thr variant (rs193922228) has been reported in multiple individuals affected with Marfan syndrome or FBN1-related disorders (Attanasio 2008, Comeglio 2007, Katzke 2002, Liu 1997, Proost 2015, Soylen 2009, Stheneur 2009), and is classified as pathogenic/likely pathogenic in ClinVar (variant ID 36107). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism). The isoleucine at codon 2269 is a highly conserved residue located within the calcium-binding EGF-like domain. Based on the above information, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2023	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; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; 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); This variant is associated with the following publications: (PMID: 10464652, 16342915, 24793577, 17657824, 25907466, 12938084, 18435798, 12203992, 19159394, 27611364, 35058154, 19293843, 31098894, 29848614) -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2021

The p.I2269T pathogenic mutation (also known as c.6806T>C), located in coding exon 55 of the FBN1 gene, results from a T to C substitution at nucleotide position 6806. The isoleucine at codon 2269 is replaced by threonine, an amino acid with similar properties, and is located in the cbEGF-like #35 domain. This variant has been detected in multiple individuals with a clinical diagnosis of Marfan syndrome (MFS) and was reported to be de novo in two of the probands (Katzke S et al, Hum. Mutat. 2002; 20(3):197-208; Attanasio M et al, Clin. Genet. 2008l; 74(1):39-46; Söylen B et al, Clin. Genet. 2009; 75(3):265-70; Stheneur C et al. Eur. J. Hum. Genet. 2009;17:1121-8; Proost D et al. Hum. Mutat. 2015;36:808-14). This variant has also been identified in several cohorts with aortic or connective tissue disease (Liu WO et al, Genet. 1997/98; 1(4):237-42; Comeglio P et al. Hum. Mutat. 2007;28:928; Yang H et al. Sci Rep. 2016;6:33002). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 01, 2017

Variant summary: The FBN1 c.6806T>C (p.Ile2269Thr) variant involves the missense alteration of a conserved nucleotide. The variant falls within a highly conserved EGF-like calcium binding domain #35 and 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in the large control population ExAC (0/121388 control chromosomes). Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic or pathogenic, and numerous publications in the literature have reported the variant in affected individuals, including 2 cases where patients had the variant as a de novo mutational event. Taken together, this variant is 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

Nov 02, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2269 of the FBN1 protein (p.Ile2269Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 10464652, 12203992, 16342915, 18435798, 19159394, 19293843, 25907466, 27611364). ClinVar contains an entry for this variant (Variation ID: 36107). 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.74

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.86

Sift

Uncertain

0.012

Sift4G

Uncertain

0.0080

Vest4

0.94

MutPred

0.84

Loss of stability (P = 0.0044);

MVP

0.97

MPC

1.4

ClinPred

0.99

GERP RS

5.9

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

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