chr15-48468527-A-T

Variant names:

• chr15-48468527-A-T
• rs193922205
• NM_000138.5:c.4467T>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000138.5(FBN1):​c.4467T>A​(p.Asn1489Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1489S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:2
• Conservation: PhyloP100: 0.813

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain EGF-like 26; calcium-binding (size 40) in uniprot entity FBN1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48468528-T-C is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 15-48468527-A-T is Pathogenic according to our data. Variant chr15-48468527-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48468527-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.4467T>A	p.Asn1489Lys	missense_variant	Exon 37 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4467T>A	p.Asn1489Lys	missense_variant	Exon 36 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4467T>A	p.Asn1489Lys	missense_variant	Exon 37 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Feb 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBN1 c.4467T>A; p.Asn1489Lys variant (rs193922205) is reported in individuals with features of Marfan syndrome (Baetens 2011, Brautbar 2010) and is reported to segregate with thoracic aortic aneurysms and dissections (TAAD) in three affected individuals of a family (Regalado 2016). This variant is reported in ClinVar (Variation ID: 36076). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.693). The asparagine at codon 1489 is a well conserved residue of the EGF consensus sequence and is critical for calcium binding (Wu 1995). Based on available information, this variant is considered to be likely pathogenic. References: Baetens M et al. Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat. 2011 Sep;32(9):1053-62. PMID: 21542060. Brautbar A et al. FBN1 mutations in patients with descending thoracic aortic dissections. Am J Med Genet A. 2010 Feb;152A(2):413-6. PMID: 20082464. Regalado ES et al. FBN1 variants in familial thoracic aortic aneurysms and dissections. Clin Genet. 2016 Jun;89(6):719-23. PMID: 26621581. Wu YS et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem Biol. 1995 Feb;2(2):91-7. PMID: 9383409. -

Sep 19, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported to segregate with aortic aneurysm and/or aortic dissection in three members from a single family without a clinical diagnosis of Marfan syndrome (Regalado et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24793577, 30371227, 25907466, 20082464, 26621581, 21542060, 20591885, 35058154) -

Marfan syndrome Pathogenic:1 Uncertain:1

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Uncertain significance

Review Status: flagged submission

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, PS1, PP4 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Oct 28, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N1489K variant (also known as c.4467T>A), located in coding exon 36 of the FBN1 gene, results from a T to A substitution at nucleotide position 4467. The asparagine at codon 1489 is replaced by lysine, an amino acid with some similar properties. This variant was described in a patient reported to have a diagnosis of Marfan syndrome (MFS) (Baetens M et al. Hum Mutat. 2011;32(9):1053-62). It was also reported in a patient with primary descending thoracic aortic dissection who did not fulfill clinical criteria for MFS (Brautbar A et al. Am J Med Genet A. 2010;152A(2):413-6). In another family, this alteration was identified three individuals reported to have aortic aneurysm or dissection (Regalado ES at al. Clin Genet. 2016;89(6):719-23). This variant was previously reported in the SNPDatabase as rs193922205. It was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), Exome Aggregation Consortium (ExAC) and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta Pathogenic:1

Jan 20, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

May 22, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.4467T>A (p.Asn1489Lys) results in a non-conservative amino acid change located in the EGF-like calcium-binding and EGF-like domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251118 control chromosomes. c.4467T>A has been reported in the literature in individuals affected with Marfan Syndrome (examples- Baetens_2011, Regalado_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21542060, 20082464, 24793577, 25907466, 26621581, 30371227, 35058154). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 . Multiple laboratories reported the variant with conflicting assessments: Pathogenic (n=1), Likely Pathogenic (n=4) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1489 of the FBN1 protein (p.Asn1489Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 20082464, 21542060, 26621581; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36076). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Feb 11, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.38	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Vest4		0.93
MutPred		0.78		Gain of ubiquitination at N1489 (P = 0.0146);
MVP		0.93
MPC		1.4
ClinPred		0.98	D
GERP RS		2.1

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: rs193922205; hg19: chr15-48760724;