rs1555400278

Variant names:

• chr15-48513581-T-C
• rs1555400278
• NM_000138.5:c.1556A>G
• FBN1 p.Tyr519Cys

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP2 PP3 PP1 PM2_Supporting PS4 PM1 PS2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA392342185/MONDO:0007947/022

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Marfan syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen, Genomics England PanelApp
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Specifications for FBN1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.1556A>G	p.Tyr519Cys	missense	Exon 13 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.1556A>G	p.Tyr519Cys	missense	Exon 12 of 65	NP_001393645.1	P35555

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.1556A>G	p.Tyr519Cys	missense	Exon 13 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.1556A>G		non_coding_transcript_exon	Exon 13 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000674301.2		n.1556A>G		non_coding_transcript_exon	Exon 13 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	2	-	Marfan syndrome (4)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Mutation Taster		=18/82	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555400278;

hg19: chr15-48805778;