15-48437827-C-T

Variant names:

• chr15-48437827-C-T
• rs1555395261
• NM_000138.5:c.6254G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 10 ACMG points: 10P and 0B. PP2 PP3 PP4 PM2_Supporting PS4_Moderate PM1 PM5

This summary comes from the ClinGen Evidence Repository: NM_000138.5 c.6254G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2085 (p.Cys2085Tyr). This variant was found in a proband with a phenotype that satisfies the revised Ghent criteria for a clinical diagnosis of Marfan syndrome (MFS) (PP4; PMID:25907466). It has been identified in another individual who meets clinical diagnostic criteria for MFS and one who does not meet diagnostic criteria but has thoracic aortic aneurysm (TAA) and a systemic score of 4 (PS4_moderate; PMID:29768367; Bichat internal data). It has been reported 2 times in ClinVar as likely pathogenic (1) and of uncertain significance (1) (Variation ID: 547338). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant alters a cysteine in a TGFβ binding-protein-like (TB) domain, in which cysteine residues are believed to form disulfide bridges important for proper protein folding (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (PP3; REVEL = 0.886). A different variant at the same amino acid position (c.6253T>G:p.Cys2085Gly) has been identified in at least two individuals with TAA and ectopia lentis and is classified as pathogenic or likely pathogenic; this further supports the functional importance of this amino acid position (PM5; Invitae internal data). The constraint z-score for missense variants affecting FBN1 is 8.2 (PP2; gnomAD v4.1.0). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PP2, PP3, PP4, PM2_supporting, PS4_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA392337017/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.89
• Publications: 1 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: Likely_pathogenic. The variant received 10 ACMG points.

• 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.
• PM5: 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.
• PP4: 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.6254G>A	p.Cys2085Tyr	missense	Exon 51 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.6254G>A	p.Cys2085Tyr	missense	Exon 50 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.6254G>A	p.Cys2085Tyr	missense	Exon 51 of 66	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.6254G>A		non_coding_transcript_exon	Exon 51 of 67	ENSP00000453958.2
	FBN1	ENST00000537463.6	TSL:5	n.*2017G>A		non_coding_transcript_exon	Exon 26 of 31	ENSP00000440294.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Marfan syndrome (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Benign	0.97
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-9.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.019	D
Vest4		0.91
MutPred		0.95		Loss of methylation at K2088 (P = 0.0536)
MVP		0.95
MPC		1.8
ClinPred		1.0	D
GERP RS		4.7
Mutation Taster		=0/100	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

Other links and lift over

dbSNP: rs1555395261; hg19: chr15-48730024; COSMIC: COSV108148089; COSMIC: COSV108148089;