15-48515402-G-A

Variant names:

• chr15-48515402-G-A
• rs137854485
• NM_000138.5:c.1453C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP2 PM2_Supporting PS4 PP1_Strong PM1 PS2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_00138 c.1453C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 485 (p.Arg484Cys). This variant has been identified in the literature in at least seven probands with features consistent with or suggestive of Marfan syndrome including thoracic aortic aneurysm and dissection (TAAD) with or without additional features (PS4; PMIDs: 16342915, 19293843, 24793577, 30485715). It was found in the homozygous state in two cousins with bilateral ectopia lentis (EL) and additional features of Marfan syndrome; of note, in both instances the variant was inherited from mildly affected or apparently unaffected heterozygous parents (PMID:17568394). It was identified in trans with a different FBN1 pathogenic variant in three siblings with isolated EL (Bichat internal data); clinical information for the heterozygous parents was not available. The variant has also been identified in the heterozygous state in 5 additional internal probands diagnosed with TAAD with or without systemic features (UZG, Johns Hopkins University, Bichat, & University of Tokyo internal data). It has been found to segregate in the heterozygous state with features of Marfan syndrome in at least 19 individuals among five different families (PP1_strong; PMID:30485715; Johns Hopkins & Bichat internal data). It has been identified as de novo once with confirmed maternity/paternity in an internal proband with a non-specific phenotype (PS2_supporting; PMID:19293843; UZG 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 are unclear about the variant’s predicted impact on the protein’s structure or function. 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, PP1_strong, PM1, PS2_supporting, PM2_supporting, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA012160/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 2.16
• Publications: 9 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 Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

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

ACMG classification

Our verdict: Pathogenic. The variant received 13 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.1453C>T	p.Arg485Cys	missense	Exon 12 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.1453C>T	p.Arg485Cys	missense	Exon 11 of 65	NP_001393645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.1453C>T	p.Arg485Cys	missense	Exon 12 of 66	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.1453C>T		non_coding_transcript_exon	Exon 12 of 67	ENSP00000453958.2
	FBN1	ENST00000674301.2		n.1453C>T		non_coding_transcript_exon	Exon 12 of 68	ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Familial thoracic aortic aneurysm and aortic dissection (2)
2	-	-	Marfan syndrome (2)
1	-	-	MARFAN SYNDROME, AUTOSOMAL RECESSIVE (1)
1	-	-	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.50	D
PhyloP100		2.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.020	D
Vest4		0.90
MutPred		0.76		Loss of disorder (P = 0.1379)
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		5.9
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137854485; hg19: chr15-48807599;