rs363811
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4PP2PM2_SupportingPS4PP1_Strong
This summary comes from the ClinGen Evidence Repository: The NM_000138.5 c.7540G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine acid by arginine at amino acid 2514 (p.Gly2514Arg), located within a calcium binding EGF-like (cbEGF) domain of the protein. This variant was found in a proband with thoracic aortic aneurysm and ectopia lentis which is a highly specific phenotype for Marfan syndrome (internal data-Bichat) (PP4). This variant has been reported in at least 4 individuals with thoracic aortic aneurysm and/or clinical features of Marfan syndrome (PMID 26272055, 19720936, 11875032, Laboratory for Molecular Medicine ClinVarentry), and in at least 3 individuals clinically diagnosed with Marfan syndrome (PMID 33483584, 28468757, Rurali et al. 2019) (PS4). It was also found to segregate with the disease in at least 5 affected family members from multiple families (Rurali et al. 2019, Laboratory for Molecular Medicine ClinVar entry, internal data) (PP1_Strong). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.945) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_Strong, PM2_Sup, PP2, PP3, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA017250/MONDO:0007947/022
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:3Uncertain:1
The NM_000138.5 c.7540G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine acid by arginine at amino acid 2514 (p.Gly2514Arg), located within a calcium binding EGF-like (cbEGF) domain of the protein. This variant was found in a proband with thoracic aortic aneurysm and ectopia lentis which is a highly specific phenotype for Marfan syndrome (internal data-Bichat) (PP4). This variant has been reported in at least 4 individuals with thoracic aortic aneurysm and/or clinical features of Marfan syndrome (PMID 26272055, 19720936, 11875032, Laboratory for Molecular Medicine ClinVarentry), and in at least 3 individuals clinically diagnosed with Marfan syndrome (PMID 33483584, 28468757, Rurali et al. 2019) (PS4). It was also found to segregate with the disease in at least 5 affected family members from multiple families (Rurali et al. 2019, Laboratory for Molecular Medicine ClinVar entry, internal data) (PP1_Strong). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.945) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_Strong, PM2_Sup, PP2, PP3, PP4 -
PM2, PP2, PP3, PP5 -
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not provided Pathogenic:3Uncertain:1
FBN1: PS4, PM1, PM2, PM5, PP3 -
The FBN1 c.7540G>A; p.Gly2514Arg variant (rs363811) is reported in the literature in several individuals affected with Marfan syndrome or thoracic aortic aneurysm/dissection (Guo 2015, Ng 2002, Pilop 2009, Rurali 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 2514 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.945). However, due to limited information, the clinical significance of the p.Gly2514Arg variant is uncertain at this time. References: Guo J et al. Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD. Sci Rep. 2015 Aug 14;5:13115. PMID: 26272055. Ng PC and Henikoff S. Accounting for human polymorphisms predicted to affect protein function. Genome Res. 2002 Mar;12(3):436-46. PMID: 11875032. Pilop C et al. Proteomic analysis in aortic media of patients with Marfan syndrome reveals increased activity of calpain 2 in aortic aneurysms. Circulation. 2009 Sep 15;120(11):983-91. PMID: 19720936. Rurali E et al. Soluble EMMPRIN levels discriminate aortic ectasia in Marfan syndrome patients. Theranostics. 2019 Apr 12;9(8):2224-2234. PMID: 31149040. -
PS4, PM2_supporting, PP2, PP3 -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located in a cb-EGF-like domain at a glycine residue that is highly conserved across other similarly structured domains in the fibrillin-1 protein; This variant is associated with the following publications: (PMID: 24941995, 31227806, 19720936, 26272055, 11875032, 19561590, 33824467, 12938084, 33483584) -
Isolated thoracic aortic aneurysm Pathogenic:1
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Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Variant summary: FBN1 c.7540G>A (p.Gly2514Arg) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) 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 251264 control chromosomes (gnomAD). c.7540G>A has been reported in individuals diagnosed with Marfan Syndrome with aortic/cardiovascular phenotypes and without ocular phenotypes (example: Pilop_2009, Franken_2017, and Gezdirici_2021). At-least one individual is reported with sporadic thoracic aortic aneurysm and dissection (example: Guo_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3), Pathogenic (n=1) and Likely Pathogenic (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
FBN1-related disorder Pathogenic:1
The FBN1 c.7540G>A variant is predicted to result in the amino acid substitution p.Gly2514Arg. This variant was reported in multiple individuals with Marfan syndrome (see for example - Ng et al. 2002. PubMed ID: 11875032; Guo et al. 2015. PubMed ID: 26272055; Gezdirici et al. 2021. PubMed ID: 33483584). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic by multiple laboratories including the ClinGen FBN1 Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/178034/). This variant is interpreted as pathogenic. -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2514 of the FBN1 protein (p.Gly2514Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with FBN1-related conditions (PMID: 11875032, 19720936, 26272055). ClinVar contains an entry for this variant (Variation ID: 178034). 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. -
not specified Uncertain:1
The Gly2514Arg variant in FBN1 has been reported in two individuals with Marfan syndrome (Ng 2002, Kumar 2009, Pilop 2009). In addition, this variant has been i dentified in 0.6% (3/336) of Asian chromosomes, 0.6% (1/180) of Luhya Kenyan chr omosomes, 2% (2/98) of Mexican chromosomes, and 0.6% (1/176) of Tuscan chromosom es by the HapMap Project (dbSNP rs363811). Computational analyses (biochemical a mino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly2514Arg variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. Furthermore, this variant has segre gated between a mother and daughter with clinical features of Marfan syndrome (L MM unpublished data), suggesting a pathogenic role. In summary, due to the confl icting information available, additional studies are needed to fully assess the clinical significance of the Gly2514Arg variant. -
Cardiovascular phenotype Uncertain:1
The p.G2514R variant (also known as c.7540G>A), located in coding exon 60 of the FBN1 gene, results from a G to A substitution at nucleotide position 7540. The glycine at codon 2514 is replaced by arginine, an amino acid with dissimilar properties.In one study,this variant was reported in a individual affected withMarfansyndrome based on personal communication with investigator P.Oefner (Ng PC et al,Genome Res.2002 Mar; 12(3):436-46). This variant was alsoreported in a 22 year old male Chinese presented with thoracic aortic aneurysms, aortic regurgitation, mitral valve regurgitation and tricuspid valve regurgitation (Guo J et al,Sci Rep2015; 5:13115).This variant was previously reported in the SNPDatabase as rs363811. <span style="font-family:arial,sans-serif; font-size:10pt">This variant was not reported in population based cohorts in the following databases: NHLBIExomeSequencing Project (ESP)and 1000 Genomes Project. In the ESP, this variant was not observed in <span style="color:#000000"><span style="font-family:arial,sans-serif; font-size:10pt">6494<span style="font-family:arial,sans-serif; font-size:10pt">samples (<span style="font-family:arial,sans-serif; font-size:10pt">12988<span style="font-family:arial,sans-serif; font-size:10pt"><span style="color:#000000"> alleles) with coverage at this position.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. <br /> -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at