rs147195031
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM6PM1PS4PP1_StrongPP2PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_00138 c.7726C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 2576 (p.Arg2576Cys) within a calcium binding EGF-like domain of the protein (PM1). This variant was found in a proband with aortic aneurysm and dissection and ectopia lentis, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data; PP4). This variant has been reported nine times in ClinVar: five times as pathogenic, three times as likely pathogenic, and once as uncertain significance (Variation ID: 36118). This variant has also been identified in at least 9 individuals with clinical diagnosis of MFS as well as in individuals with clinical features of MFS (PMID 24161884, 31830381, 33711475, 23278365, 33824467, 37042257, internal lab data; PS4). In three individuals with MFS, this variant was reported to be de novo, without confirmation of parental relationships (internal lab data, Prevention Genetics ClinVar, PM6). In at least 5 families with MFS, the variant was found to segregate with MFS and/or clinical features of MFS in several affected relatives (Internal lab data, Laboratory Corporation of America ClinVar, PP1_Strong). This variant is present in in 1/250782 (0.0004%) of alleles tested in gnomAD but did not pass the quality control criteria in the exome subset (PM2_Sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant’s protein function and structure (REVEL: 0.686). 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, PM1, PM6, PM2_Sup, PP2, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA017349/MONDO:0007947/022
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461742Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727170
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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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 (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16571647, 17701892, 12938084, 24698609, 26787436, 16677079, 15161917, 4750422, 26272055, 33824467, 23278365, 24161884) -
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Marfan syndrome Pathogenic:1Uncertain:1
The NM_00138 c.7726C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 2576 (p.Arg2576Cys) within a calcium binding EGF-like domain of the protein (PM1). This variant was found in a proband with aortic aneurysm and dissection and ectopia lentis, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data; PP4). This variant has been reported nine times in ClinVar: five times as pathogenic, three times as likely pathogenic, and once as uncertain significance (Variation ID: 36118). This variant has also been identified in at least 9 individuals with clinical diagnosis of MFS as well as in individuals with clinical features of MFS (PMID 24161884, 31830381, 33711475, 23278365, 33824467, 37042257, internal lab data; PS4). In three individuals with MFS, this variant was reported to be de novo, without confirmation of parental relationships (internal lab data, Prevention Genetics ClinVar, PM6). In at least 5 families with MFS, the variant was found to segregate with MFS and/or clinical features of MFS in several affected relatives (Internal lab data, Laboratory Corporation of America ClinVar, PP1_Strong). This variant is present in in 1/250782 (0.0004%) of alleles tested in gnomAD but did not pass the quality control criteria in the exome subset (PM2_Sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant’s protein function and structure (REVEL: 0.686). 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, PM1, PM6, PM2_Sup, PP2, PP4 -
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Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The p.R2576C pathogenic mutation (also known as c.7726C>T), located in coding exon 62 of the FBN1 gene, results from a C to T substitution at nucleotide position 7726. The arginine at codon 2576 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #41 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 variant has been detected in several individuals with Marfan syndrome (MFS), in MFS cohorts, and in individuals with aortic aneurysm/dissection or other features of MFS (Aalberts JJ et al. Gene. 2014;534(1):40-3; Baudhuin LM et al. J Hum Genet. 2015 May;60(5):241-52; Guo J. Sci Rep. 2015 Aug;5:13115; Franken R et al. Eur Heart J. 2016 Nov;37(43):3285-3290; Li Y et al. Eur J Hum Genet. 2021 07;29(7):1129-1138; Ambry internal data). This variant was observed in a homozygous patient with severe features of MFS and other clinical findings; however, the patient's heterozygous mother reportedly did not have MFS phenotype (Hogue J et al. Clin Genet. 2013;84(4):392-3). Based on internal structural analysis, this variant may interfere with disulfide formation by forming alternative disulfide bonds, thereby perturbing the structure of a flexible loop; however, the role of this loop and its structure on the function of FBN1 is unclear (Bersch B et al. Biochemistry, 1998 Feb;37:1204-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Variant summary: FBN1 c.7726C>T (p.Arg2576Cys) results in a non-conservative amino acid change, introducing a novel cysteine in the EGF-like domain (IPR000742), which is functionally important to form disulfide bonds in FBN1. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-06 in 1461742 control chromosomes (gnomAD). This variant was found to co-segregate with Marfan Syndrome in 3 patients in our internal testing family with detailed clinical information. Additionally, c.7726C>T has been reported in the literature in at least three individuals affected with Marfan Syndrome who met Ghent criteria (e.g. Aalberts_2014, Xu_2020, Mariucci_2021), one suspected MFS patient who didn't meet Ghent criteria (Baudhuin_2015), and in at least one individual with sporadic thoracic aortic aneurysm and dissections (e.g. Guo_2015). These data indicate that the variant is very likely to be associated with disease. The variant has also been reported in the homozygous state in a patient who had clinical features that were not considered typical for Marfan Syndrome and a lack of MFS symptoms in her parents (mother confirmed to carry this variant in heterozygous state; Hogue_2012) which suggests the pathogenicity of this variant in dominant form may be modified in certain conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24161884, 25652356, 26787436, 26272055, 23278365, 33824467, 33711475, 31830381). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classified the variant as pathogenic/likely pathogenic and two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Isolated thoracic aortic aneurysm Pathogenic:1
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Marfan syndrome, autosomal recessive Pathogenic:1
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FBN1-related disorder Pathogenic:1
The FBN1 c.7726C>T variant is predicted to result in the amino acid substitution p.Arg2576Cys. This variant was reported in multiple individuals with Marfan syndrome and/or related aortopathies (Table S1, Aalberts et al. 2014. PubMed ID: 24161884; Guo et al. 2015. PubMed ID: 26272055; Table S2, Franken et al. 2016. PubMed ID: 26787436; Table S3, Li. 2021 et al. PubMed ID: 33824467). This variant was also documented in the apparently homozygous state in an individual with severe Marfan syndrome. The mother was reported to be a heterozygous carrier without clinical features of Marfan syndrome and the father was not available for examination (Hogue et al. 2013. PubMed ID: 23278365). At PreventionGenetics, this variant was identified to have occurred de novo in an individual with Marfan syndrome (internal data). This variant creates a cysteine residue that is located within the epidermal growth factor-like domain of the FBN1 protein and missense variants in FBN1 that substitute or create a cysteine residue are well-documented to cause Marfan syndrome (Dietz and Dietz. 1993. PubMed ID: 20301510; Comeglio et al. 2007. PubMed ID: 17657824; Stheneur et al. 2009. PubMed ID: 19293843). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. 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 2576 of the FBN1 protein (p.Arg2576Cys). This variant is present in population databases (rs147195031, gnomAD 0.01%). This missense change has been observed in individuals with Marfan syndrome (PMID: 23278365, 24161884, 26272055, 26787436; internal data). ClinVar contains an entry for this variant (Variation ID: 36118). 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