15-48488233-C-T

Variant names:

• chr15-48488233-C-T
• rs137854478
• NM_000138.5:c.3217G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.3217G>A​(p.Glu1073Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1073G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.91
• Publications: 14 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: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain 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 chr15-48488232-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2946781.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 Marfan syndrome, Weill-Marchesani syndrome 2, dominant, progeroid and marfanoid aspect-lipodystrophy syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, stiff skin syndrome, familial thoracic aortic aneurysm and aortic dissection, isolated ectopia lentis, ectopia lentis 1, isolated, autosomal dominant, Acromicric dysplasia, neonatal Marfan syndrome, Weill-Marchesani syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 15-48488233-C-T is Pathogenic according to our data. Variant chr15-48488233-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.3217G>A	p.Glu1073Lys	missense	Exon 27 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.3217G>A	p.Glu1073Lys	missense	Exon 26 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.3217G>A	p.Glu1073Lys	missense	Exon 27 of 66	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.3217G>A		non_coding_transcript_exon	Exon 27 of 67	ENSP00000453958.2
	FBN1	ENST00000674301.2		n.3217G>A		non_coding_transcript_exon	Exon 27 of 68	ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 17, 2016

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:2

May 02, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu1073Lys is a known pathogenic variant that has been reported mostly in patients with neonatal Marfan syndrome, but also in patients 10 months – 2 years old (Nijbroek 1995, Putnam 1996, Tiecke 2001, Loeys 2004, Ades 2006, Faivre 2009, Stheneur 2009). This variant meets Ghent criteria for causal FBN1 variants, as it disrupts glutamic acid in a calcium-binding Epidermal Growth Factor-like (cbEGF) domain (Loeys 2010). In vitro functional assays with p.Glu1073Lys variant showed normal secretion (Reinhard 2000, Whiteman 2007,) but increased proteolytic cleavage suggesting structural effects of the variant and reduced ability to interact with heparin (Reinhard 2000, Kirschner 2011), The secreted fibrillin was not incorporated into the pericellular matrix (Putnam 1996).

Apr 10, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate increased susceptibility to proteolytic decay as compared to wild type (Reinhardt et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A different missense change at this residue (E1073D) has been reported in the published literature in association with neonatal Marfan syndrome (Wang et al., 1996); Reported as pathogenic in ClinVar (ClinVar Variant ID#16457; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21784848, 10766875, 17324963, 7611299, 27914124, 8882780, 16596670, 28497657)

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jan 11, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1073K pathogenic mutation (also known as c.3217G>A), located in coding exon 26 of the FBN1 gene, results from a G to A substitution at nucleotide position 3217. The glutamic acid at codon 1073 is replaced by lysine, an amino acid with similar properties, and is located in the cb EGF-like #12 domain. This alteration has been reported in multiple neonatal Marfan syndrome (MFS) cases, several times with a likely de novo origin (Nijbroek G et al. Am. J. Hum. Genet. 1995;57:8-21; Putnam EA et al. Am. J. Med. Genet. 1996;62:233-42; Adès LC et al. Am. J. Med. Genet. A. 2006;140:1047-58; Pees C et al. Clin. Genet. 2014;86:552-7; Maeda J et al. Heart Vessels. 2016;31:1717-23; Heo JS et al. J. Korean Med. Sci. 2017;32:1-3). In addition, functional studies have suggested that protein with this alteration is more susceptible to proteolytic degradation compared to wildtype and is not effectively incorporated into the extracellular matrix (Milewicz DM et al. J. Clin. Invest. 1992;89:79-86; Reinhardt DP et al. J. Biol. Chem. 2000;275:12339-45; Kirschner R et al. J. Biol. Chem. 2011;286:32810-23). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Loeys-Dietz syndrome Pathogenic:1

May 17, 2016

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Neonatal Marfan syndrome Pathogenic:1

May 15, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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

May 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FBN1 function (PMID: 10766875, 17324963, 21784848). 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. ClinVar contains an entry for this variant (Variation ID: 16457). This missense change has been observed in individuals with Marfan syndrome (PMID: 7611299, 8880577, 8882780, 11175294, 16596670). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1073 of the FBN1 protein (p.Glu1073Lys).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.030	D
Vest4		0.97
MutPred		0.93		Gain of methylation at E1073 (P = 0.0019)
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		6.2
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137854478; hg19: chr15-48780430; COSMIC: COSV100356648;