rs1555398835
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.2860C>T(p.Arg954Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,828 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 (★★).
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461828Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727214
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:6
The FBN1 c.2860C>T; p.Arg954Cys variant is reported in the literature in patients with Marfan syndrome and Marfan-related disorders (Comeglio 2007, Deng 2008, Hung 2009, Stheneur 2009) and is reported on the FBN1 Universal Mutation Database (UMD). This variant is absent from the general population (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in a highly conserved residue in one of the TGF-beta binding (TB) domains (Yuan 1997), and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. TB domains contain eight conserved cysteine residues and the disulfide bridges formed between these residues are essential for protein folding; addition of a cysteine may interfere with proper disulfide bridge formation, disrupting protein structure. Accordingly, the revised Ghent nosology for Marfan syndrome lists the introduction of cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Based on the above information, this variant is considered pathogenic. References: UMD: http://www.umd.be/FBN1/ Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Deng T et al. Late-onset bilateral lens dislocation and glaucoma associated with a novel mutation in FBN1. Mol Vis. 2008 Jun 30;14:1229-33. Hung C et al. Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. Ann Hum Genet. 2009 Nov;73(Pt 6):559-67. Loeys B et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Yuan X et al. Solution structure of the transforming growth factor beta-binding protein-like module, a domain associated with matrix fibrils. EMBO J. 1997 Nov 17;16(22):6659-66. -
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Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32679894, 32209317, 31730815, 29543232, 19328768, 21332468, 19012347, 21883168, 19293843, 18615205, 19839986, 17657824, 19002209, 25907466) -
FBN1: PP1:Strong, PM2, PS4:Moderate, PP4 -
Marfan syndrome Pathogenic:4Other:1
The p.Arg954Cys variant in the FBN1 gene has been previously reported in at least 6 individuals who fulfilled the diagnostic criteria for Marfan syndrome (Radonic et al., 2011; Sheikhzadeh et al., 2012; Proost et al., 2015; Mannucci et al., 2020), as well as in individuals with ectopia lentis (Chen et al., 2022) and individuals with aortic dissection (Zhao et al., 2020). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 495582). This variant creates a cysteine residue and is located in an established functional domain of the fibrillin1 protein known as the TGF-beta binding domain. Other pathogenic/likely pathogenic variants have been described in this domain (Robinson et al., 2006). The arginine at position 954 is strongly evolutionarily conserved. Computational tools predict that the p.Arg954Cys variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg954Cys variant as pathogenic for autosomal dominant Marfan syndrome based on the information above. [ACMG evidence codes used: PS4; PM1; PM2; PP3] -
Applied ACMG criteria: PM2, PP2, PP3, PP4, PP5_strong -
PM2, PM7, PP1, PP4 -
The c.2860C>T (p.Arg954Cys) variant of the FBN1 gene has been observed in multiple individuals (>10) from Marfan syndrome (MFS) cohorts or cohorts with Marfan-related disorders (PMID: 25907466, 21883168, 21332468, 29543232, 19002209, 17657824). This variant has also been reported to segregate in a family with 4 affected individuals having isolated late onset ectopia lentis and three young (<37yo) unaffected family members, suggesting incomplete penetrance (PMID: 18615205). This variant is a cysteine creating variant located in a highly conserved residue in one of the TGF-beta binding (TB) domains. TB domains contain eight conserved cysteine residues and the disulfide bridges formed between these residues are essential for protein folding; addition of a cysteine may interfere with proper disulfide bridge formation, disrupting protein structure (PMID: 20591885). In silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.935). This variant is absent in the general population database gnomAD and interpreted as likely pathogenic /pathogenic by several submitters in ClinVar database (ClinVar ID: 495582). Another amino acid substitutions at the same position (p.Arg954His, p.Arg954Pro) have been classified as likely pathogenic/pathogenic by multiple ClinVar submitters (ClinVar ID: 200005, 961251). Therefore, the c.2860C>T (p.Arg954Cys) variant in FBN1 is classified as pathogenic. -
Variant interpretted as Likely pathogenic and reported on 07-16-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The p.R954C variant (also known as c.2860C>T), located in coding exon 24 of the FBN1 gene, results from a C to T substitution at nucleotide position 2860. The arginine at codon 954 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the TGFBP#03 domain. This variant has been detected in Marfan syndrome (MFS) cohorts, and cohorts with MFS related features; however, in several cases, clinical detail was limited or Ghent criteria was not fulfilled (Comeglio P et al. Hum. Mutat., 2007;28:928; Faivre L et al. Eur J Hum Genet. 2009;17:491-501; Sheikhzadeh S et al. Clin Genet. 2012;82:240-7; Proost D et al. Hum Mutat. 2015;36:808-14; Radonic T et al. Clin Genet. 2011;80:346-53; Weerakkody R et al. Genet Med. 2018;20:1414-1422). This variant has also been detected in a family with bilateral lens dislocation (Deng T et al. Mol Vis. 2008;14:1229-33). Other variants affecting this codon (p.R954H, c.2861G>A and p.R954L, c.2861G>T) have also been reported in association with MFS related features (Söylen B et al. Clin Genet. 2009;75:265-70; Gong B et al. Mol Genet Genomic Med. 2019;7:e00594). Based on internal structural analysis, the p.R954C variant is anticipated to disrupt a region of known function (Lee SS et al. Structure. 2004 Apr;12(4):717-29). However, 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). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 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
Variant summary: The FBN1 c.2860C>T (p.Arg954Cys) variant involves the alteration of a conserved nucleotide and is located in TB domain, which contains eight cysteine residues that form four disulfide bonds. This variant adds a new cysteine residue, which might destroy the disulfide bond formation and further influence the structure and function of FBN1 protein. 4/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 116216 control chromosomes including the large and broad populations from ExAC. In literature, this variant has been reported in several patients (at least 13) who have Marfan or Marfanoid Syndrome. In a family, this variant was found to co-segregate with late onset isolated Ectopia Lentis (Deng_2008). The authors discuss that non-conserved arginine to cysteine substitution is highly related to predominant EL regardless of their location. While in one reported Ghent-positive MFS patient, EL was noted (Faivre_2008), information regarding presence or absence of EL has not been provided in other Ghent positive patients. It has also discussed that patients with EL and a FBN1 mutation are to be categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection (Chandra_2015) and this variant meets this criteria. This variant is also found in patients that do not have isolated EL but atypical/incomplete MFS (Comeglio_2007, Radonic_2011, Sheikhzadeh_2012). Thus, this variant can lead to clinical variability and expressivity of Marfan syndrome. Based on the evidences available, this variant is classified as Pathogenic. -
FBN1-related disorder Pathogenic:1
The FBN1 c.2860C>T variant is predicted to result in the amino acid substitution p.Arg954Cys. This variant has been reported in multiple individuals with Marfan syndrome (see for example - Comeglio et al. 2007. PubMed ID: 17657824; Stheneur et al. 2009. PubMed ID: 19293843; Hung et al. 2009. PubMed ID: 19839986). This variant was shown to segregate with ectopia lentis in one family (Deng et al. 2008. PubMed ID: 18615205). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 954 of the FBN1 protein (p.Arg954Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ectopia lentis and this condition and with Marfan syndrome (PMID: 18615205, 19002209, 19293843, 19839986). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495582). 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%. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at