chr15-48437009-G-A

Position:

• chr15-48437009-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2 PP3 PP4 PM1 PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: NM_000138.5 c.6448C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 2150 (p.Arg2150Cys). This variant has been identified in more than 15 patients with features suggestive of, or consistent with, Marfan syndrome (MFS), including at least three who meet clinical diagnostic criteria for MFS and more than 10 individuals who do not meet MFS diagnostic criteria but have thoracic aortic aneurysm and dissection (TAAD), with or without additional clinical features of MFS (PS4, PP4; Bichat, University of Tokyo, UZA, Invitae, & GeneDx internal data; PMIDs: 37042257, 19161152, 37558401, 33059708, 31730815). The variant was found to segregate with a clinical diagnosis of MFS in one patient’s parent, and with mild features suggestive of MFS or another connective tissue disorder in approximately 11 affected family members between two additional families (PP1_strong; UZA & Invitae internal data); notably, this variant is associated with particularly variable expressivity and incomplete penetrance of the MFS phenotype. It is present in gnomAD with a maximum frequency of 0.0008% (1/113462 alleles European, non-Finnish; https://gnomad.broadinstitute.org/, v2.1.1). This variant introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.923). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; gnomAD v4.0.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_strong, PM1, PP2, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA016472/MONDO:0007947/022

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 8.02

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 13 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.
• PP1: 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/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6448C>T	p.Arg2150Cys	missense_variant	53/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6448C>T	p.Arg2150Cys	missense_variant	52/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6448C>T	p.Arg2150Cys	missense_variant	53/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251026 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135656

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74426

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 08, 2023	The p.R2150C variant (also known as c.6448C>T), located in coding exon 52 of the FBN1 gene in the cb EGF-like #32 domain, results from a C to T substitution at nucleotide position 6448. The arginine at codon 2150 is replaced by cysteine, an amino acid with highly dissimilar properties. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This alteration has been observed in individuals with clinical features of Marfan syndrome (Turner CL et al. Am J Med Genet A, 2009 Feb;149A:161-70, Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 17, 2022	- -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2024	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; Introduces a new 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 (PMID: 12938084); This variant is associated with the following publications: (PMID: 26332594, 19161152, 33059708, 31730815, 12938084) -
Uncertain significance, flagged submission	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 21, 2016	Variant summary: The FBN1 c.6448C>T (p.Arg2150Cys) causes a missense change involving a conserved nucleotide located in a EGF-like domain, which 4/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "damaging" outcome, although these predictions have yet to be functionally assessed. The variant alters an Arginine to Cysteine. Cysteines are vital for proper FBN1 function and alterations, although this variant creates another Cysteine instead of eliminating a Cysteine, it could lead to disruption of disulfide binding, secondary or tertiary structure, or possibly impairing fibrillin interactions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121088 (1/60544), which does not exceed the estimated maximal expected allele frequency for a pathogenic FBN1 variant of 1/8888. The variant of interest has been reported in one affected individual via a publication that does not fulfill the Ghent criteria. In addition, the variant of interest has been cited by multiple clinical diagnostic laboratories/databases with a classification of "uncertain significance." Therefore, due to the nature of this variant, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Pathogenic," until additional information becomes available. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2150 of the FBN1 protein (p.Arg2150Cys). This variant is present in population databases (rs76702162, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 19161152, 31730815; Invitae). ClinVar contains an entry for this variant (Variation ID: 200084). 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 95%. This variant disrupts the p.Arg2150 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 28973303, 31098894; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.64	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Vest4		0.89
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8

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: rs76702162; hg19: chr15-48729206; COSMIC: COSV57312375; COSMIC: COSV57312375;