15-48437827-C-T

Variant names:

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

Variant summary

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

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

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 Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6254G>A	p.Cys2085Tyr	missense_variant	Exon 51 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6254G>A	p.Cys2085Tyr	missense_variant	Exon 50 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6254G>A	p.Cys2085Tyr	missense_variant	Exon 51 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2 Uncertain:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PS5, PP4 -

Aug 22, 2024

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

not provided Pathogenic:1

Aug 07, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with Marfan syndrome in published literature (PMID: 25907466); Not observed at significant frequency in large population cohorts (gnomAD); Affects a cysteine residue within a TGF-binding protein domain (aka TB domain or 8-Cysteine domain) and is expected to disrupt disulfide bonding within this domain; other missense substitutions that affect cysteine residues within this TGF-binding protein domain have been reported in association with various FBN1-related phenotypes, including Marfan syndrome (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35058154, 25907466) -

Computational scores

Source: dbNSFP v4.3

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
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

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: rs1555395261; hg19: chr15-48730024;