rs397515786

chr15-48488412-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):c.3164G>A(p.Cys1055Tyr) 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. 11/19 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. C1055W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.91

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 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr15-48488411-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549136.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 15-48488412-C-T is Pathogenic according to our data. Variant chr15-48488412-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48488412-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.3164G>A	p.Cys1055Tyr	missense_variant	26/66	ENST00000316623.10
FBN1	NM_001406716.1	c.3164G>A	p.Cys1055Tyr	missense_variant	25/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.3164G>A	p.Cys1055Tyr	missense_variant	26/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.C1055Y in FBN1 (NM_000138.5) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported in individuals affected with Marfan syndrome (Loeys B et al, 2001; Pees C et al, 2014). The p.C1055Y variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant affects a cysteine residue located within an epidermal-growth-factor (EGF) like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (Whiteman P et al, 2006; Savage Jr CR, 1973). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (Robinson P et al, 2006). The gene FBN1 contains 664 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. 7 variants within 6 amino acid positions of the variant p.C1055Y have been shown to be pathogenic, while none have been shown to be benign. The p.C1055Y missense variant is predicted to be damaging by both SIFT and PolyPhen2. The cysteine residue at codon 1055 of FBN1 is conserved in all mammalian species. The nucleotide c.3164 in FBN1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 28, 2009	- -
Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PVS2, PP4 -
Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); Reported in ClinVar as pathogenic (ClinVar Variant ID# 42327; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 11700157) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 07, 2018

This sequence change replaces cysteine with tyrosine at codon 1055 of the FBN1 protein (p.Cys1055Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Marfan syndrome (PMID: 11700157, 24199744). ClinVar contains an entry for this variant (Variation ID: 42327). Other missense substitutions at this codon (p.Cys1055Trp and p.Cys1055Gly) have been determined to be pathogenic (PMID: 11700157, 8863159, 16342915, 14586646). This suggests that the cysteine residue is critical for FBN1 protein function and that other missense substitutions at this position may also be pathogenic. This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 10486319, 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	35
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		1.0
MutPred		1.0		Loss of disorder (P = 0.0289);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.77		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515786; hg19: chr15-48780609;