rs1064794282

chr15-48497316-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.2243G>A(p.Cys748Tyr) 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. 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. C748R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.57

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, 7 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 chr15-48497317-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 15-48497316-C-T is Pathogenic according to our data. Variant chr15-48497316-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48497316-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.2243G>A	p.Cys748Tyr	missense_variant	19/66	ENST00000316623.10
FBN1	NM_001406716.1	c.2243G>A	p.Cys748Tyr	missense_variant	18/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.2243G>A	p.Cys748Tyr	missense_variant	19/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The FBN1 c.2243G>A variant has been reported in individuals affected with Marfan syndrome (Katzke et. al., 2002; Hung et. al., 2009) and one or more missense substitutions at this codon (p.Cys748Tyr and p.Cys748Arg) in affected individuals suggests that this may be a clinically significant residue (Hung CC et. al., 2009; Becerra-Muñoz VM et. al., 2018). This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (Mellody et. al., 2006; Ono RN et. al., 2009). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (Robinson PN et. al., 2006; Katzke et. al., 2002). The p.Cys748Tyr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database (Pathogenic/Likely Pathogenic). The amino acid Cys at position 748 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Cys748Tyr in FBN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 09, 2021	PS4_moderate, PM1, PM5, PP3, PP4, PM2_supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2023	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; 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); This variant is associated with the following publications: (PMID: 26770496, 28391405, 30675029, 19328768, 12203992, 12161601, 12938084, 31830381, 37203318, 19839986) -

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 22, 2021

Variant summary: FBN1 c.2243G>A (p.Cys748Tyr) results in a non-conservative amino acid change located in the EGF-like domain 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 251436 control chromosomes. c.2243G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g. Katzke_2002, Hung_2009, Xu_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, this variant disrupts one of the cysteine residues in the EGF-like domain, which are known to play an important role in protein structure and interactions with other molecules, suggesting that the variant could affect protein function (e.g. Dietz_1992). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2018

This sequence change replaces cysteine with tyrosine at codon 748 of the FBN1 protein (p.Cys748Tyr). 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 observed in individuals affected with Marfan syndrome (PMID: 12203992, 19839986, 12161601, 26770496). ClinVar contains an entry for this variant (Variation ID: 420086). The observation of one or more missense substitutions at this codon (p.Cys748Tyr and p.Cys748Arg) in affected individuals suggests that this may be a clinically significant residue (PMID: 19839986, 29357934). For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.97
MutPred		0.97		Loss of methylation at K747 (P = 0.0125);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		5.7

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: rs1064794282; hg19: chr15-48789513; COSMIC: COSV105154007;