rs147195031

chr15-48420780-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000138.5(FBN1):c.7726C>T(p.Arg2576Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2576H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:2
• Conservation: PhyloP100: 3.56

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 15-48420780-G-A is Pathogenic according to our data. Variant chr15-48420780-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36118.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr15-48420780-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.7726C>T	p.Arg2576Cys	missense_variant	63/66	ENST00000316623.10
FBN1	NM_001406716.1	c.7726C>T	p.Arg2576Cys	missense_variant	62/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.7726C>T	p.Arg2576Cys	missense_variant	63/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461742 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727170

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2022	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 (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 16571647, 17701892, 12938084, 24698609, 26787436, 16677079, 15161917, 4750422, 26272055, 23278365, 24161884, 33824467) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 28, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 25, 2022	- -

Marfan syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 02, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2022

The p.R2576C pathogenic mutation (also known as c.7726C>T), located in coding exon 62 of the FBN1 gene, results from a C to T substitution at nucleotide position 7726. The arginine at codon 2576 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #41 domain. 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 variant has been detected in several individuals with Marfan syndrome (MFS), in MFS cohorts, and in individuals with aortic aneurysm/dissection or other features of MFS (Aalberts JJ et al. Gene. 2014;534(1):40-3; Baudhuin LM et al. J Hum Genet. 2015 May;60(5):241-52; Guo J. Sci Rep. 2015 Aug;5:13115; Franken R et al. Eur Heart J. 2016 Nov;37(43):3285-3290; Li Y et al. Eur J Hum Genet. 2021 07;29(7):1129-1138; Ambry internal data). This variant was observed in a homozygous patient with severe features of MFS and other clinical findings; however, the patient's heterozygous mother reportedly did not have MFS phenotype (Hogue J et al. Clin Genet. 2013;84(4):392-3). Based on internal structural analysis, this variant may interfere with disulfide formation by forming alternative disulfide bonds, thereby perturbing the structure of a flexible loop; however, the role of this loop and its structure on the function of FBN1 is unclear (Bersch B et al. Biochemistry, 1998 Feb;37:1204-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Dec 05, 2023

Variant summary: FBN1 c.7726C>T (p.Arg2576Cys) results in a non-conservative amino acid change, introducing a novel cysteine in the EGF-like domain (IPR000742), which is functionally important to form disulfide bonds in FBN1. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-06 in 1461742 control chromosomes (gnomAD). This variant was found to co-segregate with Marfan Syndrome in 3 patients in our internal testing family with detailed clinical information. Additionally, c.7726C>T has been reported in the literature in at least three individuals affected with Marfan Syndrome who met Ghent criteria (e.g. Aalberts_2014, Xu_2020, Mariucci_2021), one suspected MFS patient who didn't meet Ghent criteria (Baudhuin_2015), and in at least one individual with sporadic thoracic aortic aneurysm and dissections (e.g. Guo_2015). These data indicate that the variant is very likely to be associated with disease. The variant has also been reported in the homozygous state in a patient who had clinical features that were not considered typical for Marfan Syndrome and a lack of MFS symptoms in her parents (mother confirmed to carry this variant in heterozygous state; Hogue_2012) which suggests the pathogenicity of this variant in dominant form may be modified in certain conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24161884, 25652356, 26787436, 26272055, 23278365, 33824467, 33711475, 31830381). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classified the variant as pathogenic/likely pathogenic and two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Isolated thoracic aortic aneurysm Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Vascular Biology, Beijing Anzhen Hospital

Sep 01, 2018

- -

Marfan syndrome, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2013

- -

FBN1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2024

The FBN1 c.7726C>T variant is predicted to result in the amino acid substitution p.Arg2576Cys. This variant was reported in multiple individuals with Marfan syndrome and/or related aortopathies (Table S1, Aalberts et al. 2014. PubMed ID: 24161884; Guo et al. 2015. PubMed ID: 26272055; Table S2, Franken et al. 2016. PubMed ID: 26787436; Table S3, Li. 2021 et al. PubMed ID: 33824467). This variant was also documented in the apparently homozygous state in an individual with severe Marfan syndrome. The mother was reported to be a heterozygous carrier without clinical features of Marfan syndrome and the father was not available for examination (Hogue et al. 2013. PubMed ID: 23278365). At PreventionGenetics, this variant was identified to have occurred de novo in an individual with Marfan syndrome (internal data). This variant creates a cysteine residue that is located within the epidermal growth factor-like domain of the FBN1 protein and missense variants in FBN1 that substitute or create a cysteine residue are well-documented to cause Marfan syndrome (Dietz and Dietz. 1993. PubMed ID: 20301510; Comeglio et al. 2007. PubMed ID: 17657824; Stheneur et al. 2009. PubMed ID: 19293843). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 22, 2023

For these reasons, this variant has been classified as Pathogenic. 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: 36118). This missense change has been observed in individuals with Marfan syndrome (PMID: 23278365, 24161884, 26272055, 26787436; Invitae). This variant is present in population databases (rs147195031, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2576 of the FBN1 protein (p.Arg2576Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.020	D
Vest4		0.93
MutPred		0.67		Loss of disorder (P = 0.0914);
MVP		0.92
MPC		1.7
ClinPred		0.98	D
GERP RS		6.0

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: rs147195031; hg19: chr15-48712977;