15-48487075-C-T

Variant names:

• chr15-48487075-C-T
• rs397515793
• NM_000138.5:c.3589G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PM6 PM1 PM5 PP4 PP2 PP3 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.3589G>A is a missense variant in FBN1 predicted to cause a substitution of an aspartic acid by asparagine at amino acid 1197 (p.Asp1197Asn). This variant impacts the first aspartic acid within a calcium-binding (cb) (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain (PM1). This variant was identified in two unrelated pediatric probands with a clinical diagnosis of Marfan syndrome (MFS), and was found to be de novo without confirmation of paternity and maternity (internal lab data, PM6, PP4, PS4_Sup). This variant has been reported three times in ClinVar: once as likely pathogenic, and twice as uncertain significance (Variation ID: 42339). This variant was found in an individual with thoracic aortic aneurysm and/or dissection (Internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different missense variant at this position, c.3589G>C p.Asp1197His, has previously been previously established as (likely) pathogenic and was reported as de novo in an individual with Marfan syndrome (PMID 19293843, PM5). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.772, PP3). This variant is located in the last nucleotide of the exon. In silico prediction programs predict that this variant may disrupt RNA splicing (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, PM5, PM6, PS4_Sup, PM2_Sup, PP2, PP3, PP4. ​ LINK:https://erepo.genome.network/evrepo/ui/classification/CA014319/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 7.82

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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.3589G>A	p.Asp1197Asn	missense_variant, splice_region_variant	Exon 29 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3589G>A	p.Asp1197Asn	missense_variant, splice_region_variant	Exon 28 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3589G>A	p.Asp1197Asn	missense_variant, splice_region_variant	Exon 29 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:1

May 23, 2024

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_00138 c.3589G>A is a missense variant in FBN1 predicted to cause a substitution of an aspartic acid by asparagine at amino acid 1197 (p.Asp1197Asn). This variant impacts the first aspartic acid within a calcium-binding (cb) (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain (PM1). This variant was identified in two unrelated pediatric probands with a clinical diagnosis of Marfan syndrome (MFS), and was found to be de novo without confirmation of paternity and maternity (internal lab data, PM6, PP4, PS4_Sup). This variant has been reported three times in ClinVar: once as likely pathogenic, and twice as uncertain significance (Variation ID: 42339). This variant was found in an individual with thoracic aortic aneurysm and/or dissection (Internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different missense variant at this position, c.3589G>C p.Asp1197His, has previously been previously established as (likely) pathogenic and was reported as de novo in an individual with Marfan syndrome (PMID 19293843, PM5). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.772, PP3). This variant is located in the last nucleotide of the exon. In silico prediction programs predict that this variant may disrupt RNA splicing (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, PM5, PM6, PS4_Sup, PM2_Sup, PP2, PP3, PP4. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jun 19, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ectopia lentis 1, isolated, autosomal dominant Pathogenic:1

Jun 08, 2024

Palindrome, Gene Kavoshgaran Aria

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Sep 30, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Asp1197Asn variant has not been reported in the literature nor identified by our laboratory . The amino acid aspartic acid (Asp) at position 1197 is highly conserved acros s evolutionarily distant species, suggesting that a change may not be tolerated. Computational analysis (AlignGVGD, SIFT, PolyPhen2) provide conflicting inform ation regarding the pathogenicity of this variant. In addition, nucleotide posit ion 3589 is the last nucleotide before the 5' donor splice site, but it is uncle ar if a change to this base would affect splicing. In the absence of additional information, such as control data, segregation studies, or functional analysis, the clinical significance of this variant cannot be determined at this time. -

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

May 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with FBN1-related conditions. 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. This variant disrupts the c.3589G nucleotide in the FBN1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 19293843). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 42339). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1197 of the FBN1 protein (p.Asp1197Asn). This variant also falls at the last nucleotide of exon 29, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	37
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.84	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.77
Sift	Benign	0.051	T
Sift4G	Uncertain	0.058	T
Vest4		0.85
MutPred		0.95		Loss of loop (P = 0.3664);
MVP		0.91
MPC		1.4
ClinPred		0.99	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515793; hg19: chr15-48779272; COSMIC: COSV57317937;