rs1555400278

chr15-48513581-T-C

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.1556A>G(p.Tyr519Cys) 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 Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:2
• Conservation: PhyloP100: 1.81

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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, 0.988
• PP5: Variant 15-48513581-T-C is Pathogenic according to our data. Variant chr15-48513581-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 549024.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-48513581-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.1556A>G	p.Tyr519Cys	missense_variant	13/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1556A>G	p.Tyr519Cys	missense_variant	12/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1556A>G	p.Tyr519Cys	missense_variant	13/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Nov 16, 2023	The NM_00138 c.1556A>G, is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 519 (p.Tyr519Cys). This variant was found in at least 7 probands with features consistent with or suggestive of Marfan syndrome including the following: one proband who met the original Ghent criteria with cardiovascular, skeletal, and skin involvement; one proband with bilateral ectopia lentis (EL) and systemic features; one proband with thoracic aortic aneurysm and dissection (TAAD); one proband with EL and systemic features; one proband with isolated EL; one proband with TAAD and systemic features; and once as de novo with confirmed maternity/paternity with bilateral EL, TAAD, and systemic features, a phenotype highly specific for Marfan syndrome (PS2_supporting, PS4; PMID: 15241795; University of Tokyo, UZG, Invitae, & Ambry internal data; ClinVar Variation ID: 5490254). The variant also segregates with features of Marfan syndrome in at least two affected family members (PP1; Invitae internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1, PS2_supporting, PM2_supporting, PP1, PP2, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Feb 16, 2022	ACMG categories: PM2,PP3,BP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (GeneReviews). (I) 0107 - This gene is predominantly associated with autosomal dominant disease while autosomal recessive forms of Marfan syndrome have been infrequently reported (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (GeneReviews, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and moderately conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional EGF domain. Additionally, the variant affects a critical residue within the EGF core (PMID: 31227806). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in three individuals with Marfan syndrome and/or aortic dilatation, including one de novo individual (PMID: 15241795; Invitae - personal communication). It should also be noted that this variant has been classified as a VUS by another clinical diagnostic laboratory; however, no justification was provided for their classification (ClinVar). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in the proband’s family. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2018

The p.Y519C variant (also known as c.1556A>G), located in coding exon 12 of the FBN1 gene, results from an A to G substitution at nucleotide position 1556. The tyrosine at codon 519 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #03 domain. In one study, this variant was detected in an individual reported to have Marfan syndrome (Loeys B et al. Hum. Mutat. 2004 Aug;24(2):140-6). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 13, 2022

This variant is not present in population databases (gnomAD no frequency). 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: 549024). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 15241795; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 519 of the FBN1 protein (p.Tyr519Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.70
MutPred		0.98		Gain of disorder (P = 0.0364);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.6

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: rs1555400278; hg19: chr15-48805778;