15-48456688-A-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000138.5(FBN1):​c.5371T>C​(p.Cys1791Arg) 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. 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. C1791Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

FBN1
NM_000138.5 missense

Scores

14
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.32
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a domain EGF-like 29; calcium-binding (size 41) in uniprot entity FBN1_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) 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 chr15-48456687-C-T is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
Variant 15-48456688-A-G is Pathogenic according to our data. Variant chr15-48456688-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN1NM_000138.5 linkc.5371T>C p.Cys1791Arg missense_variant Exon 44 of 66 ENST00000316623.10 NP_000129.3 P35555
FBN1NM_001406716.1 linkc.5371T>C p.Cys1791Arg missense_variant Exon 43 of 65 NP_001393645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN1ENST00000316623.10 linkc.5371T>C p.Cys1791Arg missense_variant Exon 44 of 66 1 NM_000138.5 ENSP00000325527.5 P35555

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Marfan syndrome Pathogenic:2
Mar 01, 2021
Centre of Medical Genetics, University of Antwerp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PM2, PVS2, PP4 -

Nov 07, 2017
Center for Medical Genetics Ghent, University of Ghent
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
Sep 09, 2022
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 24, 2018
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.C1791R variant (also known as c.5371T>C), located in coding exon 43 of the FBN1 gene, results from a T to C substitution at nucleotide position 5371. The cysteine at codon 1791 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #25 domain. This alterations has been detected in individuals reported to have Marfan syndrome or related features (Rommel K et al. Hum Mutat. 2005;26:529-39; Ogawa N et al. Am J Cardiol. 2011;108:1801-7). Other alterations affecting this amino acid, p.C1791Y and p.C1791F, have also been reported in association with Marfan syndrome (Loeys B et al. Arch Intern Med. 2001;161:2447-54; Howarth R et al. Genet Test. 2007;11:146-52). 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 internal structural assessment, this alteration eliminates a structurally critical disulfide in the structurally sensitive cbEGF-like domain #25. Furthermore, 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 alteration is likely to be pathogenic. -

not provided Pathogenic:1
Aug 27, 2018
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The C1791R pathogenic variant in the FBN1 gene has been previously reported in association with Marfan syndrome (Rommel et al., 2005; Ogawa et al., 2011). Rommel et al. (2005) identified this variant in two sisters diagnosed with classic Marfan syndrome per Ghent diagnostic criteria. Subsequently, C1791R was reported in one individual from a cohort of 53 Japanese individuals suspected of having Marfan syndrome, although further clinical details as to whether this individual fulfilled Ghent diagnostic criteria were not available (Ogawa et al., 2011). This variant is also not observed in large population cohorts (Lek et al., 2016). The C1791R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, C1791R 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). Finally, other pathogenic/likely pathogenic variants at the same residue (C1791Y, C1791F) have also been reported in association with FBN1-related disorders (Loeys et al., 2001; Howarth et al., 2007), supporting the functional importance of this residue. -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Dec 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1791 of the FBN1 protein (p.Cys1791Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 16220557; internal data). ClinVar contains an entry for this variant (Variation ID: 449439). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of 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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.61
CADD
Pathogenic
29
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Pathogenic
0.97
D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-11
D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Vest4
0.98
MutPred
0.99
Loss of catalytic residue at E1792 (P = 0.2216);
MVP
0.99
MPC
1.9
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555396427; hg19: chr15-48748885; API