15-48474369-C-T

Position:

chr15-48474369-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000138.5(FBN1):c.4096G>A(p.Glu1366Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/18 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. E1366Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (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:9

Conservation

PhyloP100: 7.67

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:

FBN1 (HGNC:):

FBN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a domain EGF-like 23; calcium-binding (size 40) in uniprot entity FBN1_HUMAN there are 18 pathogenic changes around while only 1 benign (95%) 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 chr15-48474369-C-G is described in Lovd as [Likely_pathogenic].

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, 0.994

PP5

Variant 15-48474369-C-T is Pathogenic according to our data. Variant chr15-48474369-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48474369-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.4096G>A	p.Glu1366Lys	missense_variant	34/66	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 linkuse as main transcript	c.4096G>A	p.Glu1366Lys	missense_variant	33/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.4096G>A	p.Glu1366Lys	missense_variant	34/66	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727196

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Mar 12, 2021	This variant is predicted to be damaging by insilico missense prediction tools (SIFT and Polyphen2). It was previously reported in multiple patients with Marfan syndrome [PMID: 14695540, 27611364, 27724990, 24199744, 17657824] and reported to affect calcium-binding EGF-like module [PMID: 14695540, 27611364]. -
Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS6, PP4 -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 06, 2020	The p.E1366K pathogenic mutation (also known as c.4096G>A), located in coding exon 33 of the FBN1 gene, results from a G to A substitution at nucleotide position 4096. The glutamic acid at codon 1366 is replaced by lysine, an amino acid with similar properties, and is located in the cbEGF-like domain #19. This variant has been reported in classical Marfan syndrome cases and in individuals with ectopia lentis and skeletal findings but who lacked typical cardiac findings (Biggin A et al. Hum Mutat, 2004 Jan;23:99; Comeglio P et al. Hum Mutat, 2007 Sep;28:928; Baumgartner C et al. Methods Inf Med, 2005;44:487-97; Pees C et al. Clin Genet, 2014 Dec;86:552-7; Proost D et al. Hum Mutat, 2015 Aug;36:808-14). This variant was more recently reported as de novo in a child with ectopia lentis and mild aortic dilation (Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Geleophysic dysplasia 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PS2,PM1,PM2,PP3,PP4 -

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

Dec 20, 2021

Variant summary: FBN1 c.4096G>A (p.Glu1366Lys) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. c.4096G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome to include a De-novo mode of inheritance reported in some (example, Baumgartner_2005, Biggin_2004, Comeglio_2007, Robinson_2011, Pees_2013, Proost_2015, Li_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 11, 2024

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; This variant is associated with the following publications: (PMID: 21895641, 25907466, 17657824, 27611364, 24199744, 31098894, 32123317, 34281902, 36703223, 35042684, 38190127, 36729443, 34663891, 14695540, 35058154, 34818515, 35237611, 27724990, 33844962, DumanliA2020[Article], 16342915, 31754721, Fan2009[Abstract], 33576469, 20591885) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1366 of the FBN1 protein (p.Glu1366Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 14695540, 16342915, 17657824, 24199744, 27611364, 27724990, 31098894). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 200036). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Vest4

0.96

MutPred

0.94

Gain of methylation at E1366 (P = 0.0119);

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

4.8

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