rs794728283

Positions:

• chr15-48415549-G-A

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.8038C>T​(p.Arg2680Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,138 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2680H) 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:8
• Conservation: PhyloP100: 1.72

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr15-48415548-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 527153.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 15-48415549-G-A is Pathogenic according to our data. Variant chr15-48415549-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48415549-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.8038C>T	p.Arg2680Cys	missense_variant	64/66	ENST00000316623.10
FBN1	NM_001406716.1	c.8038C>T	p.Arg2680Cys	missense_variant	63/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.8038C>T	p.Arg2680Cys	missense_variant	64/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461138 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726920

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	case-control	deCODE genetics, Amgen	Apr 10, 2023	The p.(Arg2680Cys) variant was identified in a six-generation Marfan syndrome family in Iceland. There are 21 carriers of the variant in this family, either diagnosed with Marfan syndrome and/or show clinical features consistent with Marfan syndrome. Overall p.(Arg2680Cys) appears to result in mild Marfan syndrome, but a strong predisposition to the development of abdominal aortic aneurysms. The variant associates with increased height (p-value 5.65*10-8; SD 1.46) and thoracid aortic aneurysm (p-value 0.042; OR 23.3). Applied ACMG criteria: PS4, PM2, PP2, PP4Applied ACMG criteria: PS4, PM2, PP2, PP3, PP4, PP5_strong -
Likely pathogenic, 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:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 05, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 18, 2018	The p.R2680C variant (also known as c.8038C>T), located in coding exon 63 of the FBN1 gene, results from a C to T substitution at nucleotide position 8038. The arginine at codon 2680 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #43 domain. This variant has been reported in individuals with Marfan syndrome-like features, including ocular and skeletal findings and one reportedly de novo occurrence (Palz M et al. Am. J. Med. Genet., 2000 Mar;91:212-21; Comeglio P et al. Hum. Mutat., 2007 Sep;28:928). This variant was also described in an individual with Marfan syndrome who was a compound heterozygote with an additional FBN1 variant; her son was heterozygous for only p.R2680C and was reported to have ectopia lentis at two years old, with no additional clinical features of Marfan syndrome at that time (Arnaud P et al. J. Med. Genet., 2017 02;54:100-103). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Jan 29, 2024

Variant summary: FBN1 c.8038C>T (p.Arg2680Cys) results in a non-conservative amino acid change located in the EGF like domain (IPR001881) 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 249484 control chromosomes (gnomAD). c.8038C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (examples: Collod-Beroud_1998, Palz_2000, and Klemenzdottir_2024). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 37684520, 9399842, 10756346). ClinVar contains an entry for this variant (Variation ID: 200127). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2022

Reported in the literature in association with Marfan syndrome or suspected Marfan syndrome in multiple individuals, several of whom had ectopia lentis and skeletal features without aortic dilation (Grossfield et al., 1993; Palz et al., 2000; Comeglio et al., 2007; Jin et al., 2007; Arnaud et al., 2017), and in patients referred for genetic testing at GeneDx.; 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 cysteine residue into 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: 17568394, 8653794, 9401003, 18615205, 15054843, 17657824, 27647783, 27582083, 17679947, 10756346, 27535533, 33059708, 31751304) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2680 of the FBN1 protein (p.Arg2680Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FBN1-related conditions and Marfan syndrome (PMID: 10756346, 12938084, 17657824, 27582083; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 200127). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.57	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.98
MutPred		0.86		Gain of disorder (P = 0.268);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		2.5

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: rs794728283; hg19: chr15-48707746; COSMIC: COSV100355798;