rs1555398397

Positions:

• chr15-48485436-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS4_Moderate PM1 PP2 PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.3650G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine by aspartic acid at amino acid 1217 (p.Gly1217Asp). This cysteine-creating variant impacts a critical glycine between Cys3 and Cys4 within a calcium binding EGF-like domain, important for interdomain packaging (PM1, PMID 31227806). This variant was found in a pediatric proband with a systemic score >7 and thoracic aortic dissection, which is a highly specific phenotype for Marfan syndrome (MFS) (internal lab data, PP4). In this family, the variant was found to be inherited from the probands affected father (internal lab data). This variant has been reported three times in ClinVar: once as likely pathogenic, and twice as uncertain significance (Variation ID: 549180). This variant has also been reported in at least 4 individuals with a clinical diagnosis of MFS or clinical features of MFS (PS4_Mod; PMID 27112580, Petrovsky National Research Centre of Surgery ClinVar entry, Internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.987, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). 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, PS4_Mod, PM2_Sup, PP2, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA392324483/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 7.90

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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.
• 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/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3650G>A	p.Gly1217Asp	missense_variant	30/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3650G>A	p.Gly1217Asp	missense_variant	29/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3650G>A	p.Gly1217Asp	missense_variant	30/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2 Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	May 23, 2024	The NM_00138 c.3650G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine by aspartic acid at amino acid 1217 (p.Gly1217Asp). This cysteine-creating variant impacts a critical glycine between Cys3 and Cys4 within a calcium binding EGF-like domain, important for interdomain packaging (PM1, PMID 31227806). This variant was found in a pediatric proband with a systemic score >7 and thoracic aortic dissection, which is a highly specific phenotype for Marfan syndrome (MFS) (internal lab data, PP4). In this family, the variant was found to be inherited from the probands affected father (internal lab data). This variant has been reported three times in ClinVar: once as likely pathogenic, and twice as uncertain significance (Variation ID: 549180). This variant has also been reported in at least 4 individuals with a clinical diagnosis of MFS or clinical features of MFS (PS4_Mod; PMID 27112580, Petrovsky National Research Centre of Surgery ClinVar entry, Internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.987, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). 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, PS4_Mod, PM2_Sup, PP2, PP3, PP4. -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Aug 02, 2019	The p.Gly1217Asp variant was found in one individual with MFS (PMID: 27112580) and is absent in large population studies (ExAC no frequency). The substitution of 1217 codon occurs in cbEGF-like domain and it participates in domain-domain packing (UMD-FBN1 Record ID: 2293). FBN1 gene is known to be less tolerant to missense variants (ExAC Z score = 5.33). ClinVar has an entry for this variant (Variation ID: 549180). Computational tools like Provean, PolyPhen2, MutationTaster show a deleterious result. Classification was based on ACMG criteria, concluding p.Gly1217Asp variant as Likely Pathogenic (PM1, PM2, PP2, PP3, PP4), although without function study we can't exclude the possibility of benign. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2020

This sequence change replaces glycine with aspartic acid at codon 1217 of the FBN1 protein (p.Gly1217Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in an individual affected with Marfan syndrome (PMID: 27112580). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Vest4		0.97
MutPred		0.89		Loss of catalytic residue at S1218 (P = 0.0862);
MVP		0.95
MPC		1.6
ClinPred		0.99	D
GERP RS		6.0

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: rs1555398397; hg19: chr15-48777633;