rs397515797

chr15-48481733-A-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):c.3886T>C(p.Cys1296Arg) 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. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.27

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 17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 15-48481733-A-G is Pathogenic according to our data. Variant chr15-48481733-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48481733-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.3886T>C	p.Cys1296Arg	missense_variant	32/66	ENST00000316623.10
FBN1	NM_001406716.1	c.3886T>C	p.Cys1296Arg	missense_variant	31/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.3886T>C	p.Cys1296Arg	missense_variant	32/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 30, 2013

The Cys1296Arg variant in FBN1 has not previously been identified by our laborat ory or in the literature. This variant affects a cysteine residue and cysteine s ubstitutions are a common finding in patients with Marfan syndrome (Schrijver 19 99). This variant has not been identified in large and broad African American an d European American populations by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS/). Computational analyses (biochemical amino acid proper ties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Cys1296Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant is likely pathogenic, thou gh additional studies are required to fully establish its clinical significance. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2014

The C1296R variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The C1296R variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The C1296 residue is conserved across species. In silico analysis predicts C1296R is damaging to the protein structure/function. Mutations in nearby residues (C1284G, C1284R, C1284Y, K1300E, C1307Y) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the C1296R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Lastly, Cysteine substitutions in FBN1 represent the vast majority of pathogenic missense changes associated with Marfan syndrome.In summary, while C1296R is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in TAAD panel(s). -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2020

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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). This variant has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 42344). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 1296 of the FBN1 protein (p.Cys1296Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		1.0
MutPred		0.99		Gain of ubiquitination at K1300 (P = 0.0571);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5

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: rs397515797; hg19: chr15-48773930;