15-48503845-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):c.2055C>G(p.Cys685Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C685R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 0.189

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]

ACMG classification

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 1 benign, 7 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 chr15-48503846-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 15-48503845-G-C is Pathogenic according to our data. Variant chr15-48503845-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48503845-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.2055C>G	p.Cys685Trp	missense_variant	17/66	ENST00000316623.10
FBN1	NM_001406716.1	c.2055C>G	p.Cys685Trp	missense_variant	16/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.2055C>G	p.Cys685Trp	missense_variant	17/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2015	- -
Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS5, PP4 -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2007	- -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 08, 2020

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant affects a cysteine residue located within a TGFBP domain of the FBN1 protein. Cysteine residues in these domains are believed to be involved in intramolecular disulfide bridges and to be important for FBN1 structure. Although the exact function of the FBN1 TGFBP domains has not being elucidated (PMID: 10930463, 27437668), missense substitutions within the TGFBP domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). This variant has been reported in several individuals affected with Marfan syndrome or an aortopathy (PMID: 21542060, 12203992, 15241795, 27611364). ClinVar contains an entry for this variant (Variation ID: 36043). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tryptophan at codon 685 of the FBN1 protein (p.Cys685Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. -

Marfan syndrome;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant classified as Pathogenic and reported on 10-12-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.98
MutPred		0.95		Gain of catalytic residue at C685 (P = 0.0123);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		-1.4

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

Other links and lift over

dbSNP: rs140603; hg19: chr15-48796042;