rs730880099
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.1633C>T(p.Arg545Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R545H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.1633C>T | p.Arg545Cys | missense_variant | 14/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.1633C>T | p.Arg545Cys | missense_variant | 13/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.1633C>T | p.Arg545Cys | missense_variant | 14/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461080Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726854
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 13, 2018 | The c.1633C>T (p.Arg545Cys) variant in the FBN1 gene has been reported in multiple patients and segregated in two unrelated families with Marfan syndrome (PMID: 9338581, 11700157, 17657824, 19159394, 25944730, 27353645). The variant is not observed in the gnomAD. Therefore, this c.1633C>T (p.Arg545Cys) variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 06, 2015 | - - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 09, 2021 | This missense variant replaces arginine with cysteine at codon 545 in an epidermal-growth-factor (EGF)-like domain of the FBN1 protein. Although functional studies have not been reported, this variant generates a cysteine residue in an important functional domain and is likely to affect protein structure and stability (PMID: 4750422, 16677079). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in multiple individuals affected with Marfan syndrome, ectopia lentis or aortopathy (PMID: 12446365, 15241795, 17679947, 19159394, 20564469, 27611364, 27353645). This variant has been reported to segregate with aortic dissection and ectopia lentis in ten individuals from a family affected with Marfan syndrome (PMID: 27353645). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2022 | The p.R545C pathogenic mutation (also known as c.1633C>T), located in coding exon 13 of the FBN1 gene, results from a C to T substitution at nucleotide position 1633. The arginine at codon 545 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #04 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 alteration has been described in several patients with ectopia lentis and Marfan syndrome (Loeys B et al. Arch Intern Med. 2001;161(20):2447-54; Jin C et al. Mol Vis. 2007;13:1280-4, Comeglio P et al. Hum Mutat. 2007;28(9):928). Additionally, this alteration was observed to co-segregate in multiple relatives in two unrelated multi-generation families (Hayward C et al. Hum Mutat. 1997;10(4):280-9; Li Y et al. Clin. Chim. Acta, 2016 Sep;460:102-6). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, p.R545C is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 17, 2021 | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 23, 2017 | - - |
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 | Oct 10, 2016 | Variant summary: The FBN1 c.1633C>T (p.Arg545Cys) variant involves the alteration of a highly conserved nucleotide and is located in the Ca2+-binding EGF-like #4 domain with 5/5 in silico tools predicting a deleterious outcome. This change disrupts disulfide bonds 541-555 (C4) which affects the secondary or tertiary structure and possibly impairing fibrillin interactions. The variant is absent from control dataset of ExAC and but has been reported in numerous affected individuals predominantly with isolated EL via published reports, although several pts with classical MFS have also been reported, including within families presenting with EL. Two published reports clearly indicate segregation of the variant with the disease (Hayward, 1997 and Li, 2016). The variant has been cited by several reputable databases/clinical laboratories as Pathogenic. Taking together, the variant was classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID#180352; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 11700157, 20021881, 20564469, 12446365, 27611364, 22772377, 28642162, 25053872, 31447099, 32123317, 12938084, 19159394, 27353645, 9338581, 17679947) - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 545 of the FBN1 protein (p.Arg545Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ectopia lentis and/or Marfan syndrome (PMID: 9338581, 12446365, 15241795, 17679947, 19159394, 20564469, 27353645, 27611364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180352). 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. - |
Ectopia lentis 1, isolated, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
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 | Apr 11, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at