rs111401431

chr15-48468097-G-Achr15-48468097-G-T

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.4588C>T(p.Arg1530Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging 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. R1530P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 6.62

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr15-48468096-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519692.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, 0.897
• PP5: Variant 15-48468097-G-A is Pathogenic according to our data. Variant chr15-48468097-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48468097-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.4588C>T	p.Arg1530Cys	missense_variant	38/66	ENST00000316623.10
FBN1	NM_001406716.1	c.4588C>T	p.Arg1530Cys	missense_variant	37/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.4588C>T	p.Arg1530Cys	missense_variant	38/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Nov 17, 2021	ACMG criteria used to clasify this variant: PP3, PS4, PM2, PM5, PP1, PP2 -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Marfan syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:19941982). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate. Observed in several unrelated affected individuals and absent from population databases (ExAC and gnomAD) (PMID:11700157) (PMID:17663468) (PMID:14695540) (PMID:17679947) (PMID:19941982). PP3-Moderate => PP3 upgraded in strength to Moderate. Mutation creates a cystein residue. The majority of FBN1 mutations involve substitution or creation of cystein residues. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 17, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 14, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP4 -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 26, 2020	The FBN1 c.4588C>T, p.Arg1530Cys variant (rs111401431) has been reported in multiple individuals with Marfan syndrome or Marfan-like symptoms such as ectopia lentis and aortic dissection (Aragon-Martin 2010, Biggin 2004, Howarth 2007, Jin 2007, Loeys 2001, Rand-Hendriksen 2007, Tjeldhorn 2006, Villamizar 2010, Wang 2013, Yoo 2010). It is listed as pathogenic in ClinVar (Variation ID: 36078), and not observed in the general population databases. The variant creates a novel cysteine residue in the FBN1 protein, which is considered causal for Marfan syndrome according to the revised Ghent nosology (Loeys 2010). Based on the above information, the p.Arg1530Cys variant is classified as pathogenic. References: Aragon-Martin J et al. Role of ADAMTSL4 mutations in FBN1 mutation-negative ectopia lentis patients. Hum Mutat. 2010; 31(8):E1622-31. Biggin A et al. Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat. 2004; 23(1):99. Howarth R et al. Application of dHPLC for mutation detection of the fibrillin-1 gene for the diagnosis of Marfan syndrome in a National Health Service Laboratory. Genet Test. 2007; 11(2):146-52. Jin C et al. Novel FBN1 mutations associated with predominant ectopia lentis and marfanoid habitus in Chinese patients. Mol Vis. 2007; 13:1280-4. Loeys B et al. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001; 2001 Nov 12;161(20):2447-54. Loeys B et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010; 47(7):476-85. Rand-Hendriksen S et al. Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome. Am J Med Genet A. 2007; 143A(17):1968-77. Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006; 10(4):258-64. Villamizar C et al. Paucity of skeletal manifestations in Hispanic families with FBN1 mutations. Eur J Med Genet. 2010; 53(2):80-4. Wang W et al. Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections. J Mol Med (Berl). 2013; 91(1):37-47. Yoo E et al. Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ethnic differences in clinical manifestation. Clin Genet. 2010; 77(2):177-82. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	Identified in a patient with bilateral ectopia lentis (Cappuccio et al., 2022); this patient was also hemizygous for a variant in the RPL10 gene and had a history of severe intellectual disability, dysmorphic features, retinitis pigmentosa and cryptorchidism; 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: 24698609, 23794388, 20021881, 17679947, 17627385, 20564469, 16971892, 15054843, 19941982, 22772377, 27647783, 17663468, 14695540, 17253931, 11700157, 19863550, 29768367, 29198452, 30838813, 31098894, 29357934, 31536524, 31825148, 31730815, 34818515, 24161884, 35058154, 35876338) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2015	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2022

The p.R1530C pathogenic mutation (also known as c.4588C>T), located in coding exon 37 of the FBN1 gene, results from a C to T substitution at nucleotide position 4588. The arginine at codon 1530 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 pathogenic mutation has been identified in multiple individuals with ectopia lentis (EL); some of these individuals also met Ghent criteria while some did not (Loeys B et al. Arch Intern Med. 2001;161(20):2447-54; Biggin A et al. Hum Mutat. 2004;23(1):99; Jin C et al. Mol Vis. 2007;13:1280-4; Aragon-Martin JA et al. Hum Mutat. 2010;31(8):E1622-31; Vanem TT et al. Am J Med Genet A. 2020 02;182(2):397-408). This mutation was found to co-segregate with disease in two unrelated families (Rand-Hendriksen S et al. Am J Med Genet A. 2007;143A(17):1968-77; Mannucci L et al. Clin Chim Acta. 2020 Feb;501:154-164; Villamizar C et al. Eur J Med Genet. 2010; 53(2):80-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

May 24, 2022

Variant summary: FBN1 c.4588C>T (p.Arg1530Cys) results in a non-conservative amino acid change in 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 251128 control chromosomes. c.4588C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome and the variant has been shown to segregate with disease (eg. Loeys_2001, Biggin_2004, Tjeldhorn_2006, Jin_2007, Howarth_2007, etc). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

FBN1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2023

The FBN1 c.4588C>T variant is predicted to result in the amino acid substitution p.Arg1530Cys. This variant has been reported in multiple individuals with ectopia lentis, and in some cases was determined to have arisen de novo (see for examples Loeys et al. 2001. PubMed ID: 11700157; Khan et al. 2014. PubMed ID: 24698609; Li et al. 2019. PubMed ID: 31098894). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.4588C>T (p.Arg1530Cys) as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1530 of the FBN1 protein (p.Arg1530Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 11700157, 14695540, 17253931, 17627385, 17663468, 17679947, 19863550). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36078). 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%. For these reasons, this variant has been classified as Pathogenic. -

Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.043	D
Vest4		0.95
MutPred		0.62		Loss of disorder (P = 0.0867);
MVP		0.99
MPC		0.80
ClinPred		1.0	D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111401431; hg19: chr15-48760294; COSMIC: COSV57310752; COSMIC: COSV57310752;