rs794728251
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS3PS4PP1_StrongPP3PP4PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000138.5 c.6453C>T variant in FBN1does not result in an amino acid substitution. This variant was found in a proband with thoracic aortic aneurysm and/or dissection, and a systemic score of 8, which is a highly specific phenotype for Marfan syndrome (internal data-Ghent university Hospital) (PP4). This variant has been reported 6 times in ClinVar: 4 times as pathogenic, 2 times as likely pathogenic, and once as variant of uncertain significance (Variation ID: 200193). The variant has been reported in the literature in at least two unrelated individuals with a clinical diagnosis of Marfan syndrome, and in at least four unrelated individuals with clinical features of Marfan syndrome (PMID 26787436, 36517271, 21907952, 32679894, 36517271, InvitaeClinVarentry) (PS4). This variant was also found to segregate with disease in at least 5 affected relatives from multiple families (PMID 21907952, internal data) (PP1_Strong). In silico prediction programs predict that this variant may impact splicing (PP3). RNA functional studies confirmed that this variant results in the creation of a cryptic donor splice site resulting in an abnormal truncated protein (PMID 21907952, 26787436, 32123317) (PS3). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). 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: PS3, PS4, PP1_Strong, PM2_Sup, PP3, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA016495/MONDO:0007947/022
Frequency
Consequence
NM_000138.5 synonymous
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 Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:3Uncertain:1
The c.6453C>T (p.Cys2151=) synonymous variant is located at the exon 53 of the FBN1 gene, encoding fibrillin 1. This variant has been reported in at least four individuals with clinical features of Marfan syndrome and segregated with disease in two affected relatives in one family (PMID: 21907952, 32679894, 25652356, 26787436). In-silico computational prediction tools suggest that the c.6453C>T variant likely leads to a new donor gain (SpliceAI: 0.8448) and disturb normal splicing, resulting in an aberrant protein product (PMID: 16199547). Functional studies using complementary DNA derived from aortic tissue and peripheral blood demonstrated that this variant creates a new cryptic splice donor site resulting in abnormal shorter messenger RNA with an in-frame deletion of 45 nucleotides from exon 53, named as r.6452_6496del p.(Cys2151_Asp2166delinsTyr) by the authors (PMID: 21907952, 32123317). This deletion affects multiple Cysteine residues in the calcium binding epidermal growth factor 32 domain (cbEGF32), and disulfide bridges formed between these residues are essential for protein folding (ClinGen FBN1 VCEP guidelines, PMID: 20591885). This variant is absent in the general population database (gnomAD) and classified as likely pathogenic/pathogenic by several ClinVar submitters (ClinVar ID: 200193). Therefore, the c.6453C>T (p.Cys2151=) synonymous variant in FBN1 is classified as pathogenic. -
The NM_000138.5 c.6453C>T variant in FBN1does not result in an amino acid substitution. This variant was found in a proband with thoracic aortic aneurysm and/or dissection, and a systemic score of 8, which is a highly specific phenotype for Marfan syndrome (internal data-Ghent university Hospital) (PP4). This variant has been reported 6 times in ClinVar: 4 times as pathogenic, 2 times as likely pathogenic, and once as variant of uncertain significance (Variation ID: 200193). The variant has been reported in the literature in at least two unrelated individuals with a clinical diagnosis of Marfan syndrome, and in at least four unrelated individuals with clinical features of Marfan syndrome (PMID 26787436, 36517271, 21907952, 32679894, 36517271, InvitaeClinVarentry) (PS4). This variant was also found to segregate with disease in at least 5 affected relatives from multiple families (PMID 21907952, internal data) (PP1_Strong). In silico prediction programs predict that this variant may impact splicing (PP3). RNA functional studies confirmed that this variant results in the creation of a cryptic donor splice site resulting in an abnormal truncated protein (PMID 21907952, 26787436, 32123317) (PS3). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). 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: PS3, PS4, PP1_Strong, PM2_Sup, PP3, PP4 -
FBN1 NM_000138.4 exon 53 p.Cys2151Cys (c.6453C>T): This variant has been reported in the literature in 1 individual with Marfan syndrome, segregating with disease in 2 affected relatives (Ogawa 2011 PMID:21907952). This variant is not present in large control databases. Although this is a ‘silent’ mutation, functional studies have demonstrated that this variant may result in a splice site alteration, resulting in an abnormal protein (Ogawa 2011 PMID:21907952). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. -
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not provided Pathogenic:3
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Not observed at significant frequency in large population cohorts (gnomAD); RNA studies on cDNA sequenced from aortic tissue revealed alternative splicing pattern between exon 52 and 53 creating a new splice donor site resulting in abnormally shorter mRNA (PMID: 21907952); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 21907952, 32123317, 34663891, 26787436, 32679894, 36517271) -
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Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
This sequence change affects codon 2151 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Marfan syndrome (PMID: 21907952, 26787436, 32679894; Invitae). ClinVar contains an entry for this variant (Variation ID: 200193). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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