15-48489980-C-T

Position:

chr15-48489980-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.2953G>A(p.Gly985Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/18 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. G985E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Failed GnomAD Quality Control

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.90

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 19 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 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 chr15-48489979-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16453.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, FBN1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 15-48489980-C-T is Pathogenic according to our data. Variant chr15-48489980-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48489980-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.2953G>A	p.Gly985Arg	missense_variant	25/66	ENST00000316623.10
FBN1	NM_001406716.1 linkuse as main transcript	c.2953G>A	p.Gly985Arg	missense_variant	24/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.2953G>A	p.Gly985Arg	missense_variant	25/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152096

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 31, 2017	The p.G985R variant (also known as c.2953G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 2953. The glycine at codon 985 is replaced by arginine, an amino acid with dissimilar properties, and is located in the TGFBP #03 domain. This alteration has been identified in multiple individuals with classical Marfan syndrome and reported to co-segregate with disease (Loeys B et al. Arc Intern Med. 2001;161(20):2447-54; Howarth R et al. Genet. Test., 2007;11:146-52; Ware AL et al. Cardiovasc. Pathol. 2016 Jun;25:418-22). Another study has suggested that this alteration does not co-segregate with disease (Yang H et al. Sci Rep, 2016 Sep;6:33002). An alteration affecting the same amino acid (p.G985E, c.2954G>A) has been reported in individuals with classical Marfan syndrome (Collod-Béroud G et al. Am. J. Hum. Genet., 1999 Sep;65:917-21; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8). 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 majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 08, 2023	- -

Marfan syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Center for Medical Genetics Ghent, University of Ghent

Nov 07, 2017

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 21, 2017

Variant summary: The FBN1 c.2953G>A (p.Gly985Arg) missense variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools. This variant is located in TB domain and glycines in the FBN1 gene are implicated in correct domain-domain packing (Faive_2009). This variant is absent in 121470 control chromosomes (including ExAC). This variant has been reported in several MFS (classic as well as incomplete MFS) patients. In one family, this variant was found in three affected members with MFS or MFS-like syndrome but not in five unaffected members, indicating cosegregation with disease (Howarth_2007). In two other families, probands affected with classic MFS and two first-degree relatives in each family carried the variant; however affected status of the family members was not clearly indicated (Ware_2016). In contrast to the pathogenic outcome from these three families, a study reclassified this variant to benign from family segregation analysis (Yang_2016). However, genotypic and phenotypic details of family members were not provided, limiting independent evaluation of the evidences. Two clinical diagnostic laboratories (via ClinVar) have classified this variant as likely pathogenic (one has noted the finding of Yang_2016). Another missense change at the same residue G985E has also been reported in a patient with MFS, suggesting that Gly985 codon could be mutational hot-spot. Based on the currently available data, this variant is classified as likely pathogenic. -

Isolated thoracic aortic aneurysm

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Vascular Biology, Beijing Anzhen Hospital

Sep 01, 2018

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located at a highly conserved Glycine residue in a TB domain, which may be important for protein structure/function (Collod-Beroud et al., 2003); Reported in ClinVar as pathogenic and likely pathogenic (ClinVar Variant ID# 200008; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31098894, 19002209, 19161152, 17627385, 27611364, 16220557, 19863550, 24941995, 27479044, 24199744, 11700157, 29907982, 32123317, 33059708) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 08, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 985 of the FBN1 protein (p.Gly985Arg). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 200008). This missense change has been observed in individual(s) with Marfan syndrome or FBN1-related conditions (PMID: 11700157, 16220557, 17627385, 19863550, 24199744). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Benign

0.067

Vest4

0.95

MutPred

0.95

Gain of disorder (P = 0.0808);

MVP

0.99

MPC

1.6

ClinPred

1.0

GERP RS

5.7

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