rs397515847
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.7168T>C(p.Cys2390Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2390S) has been classified as Likely pathogenic.
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.7168T>C | p.Cys2390Arg | missense_variant | 58/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.7168T>C | p.Cys2390Arg | missense_variant | 57/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.7168T>C | p.Cys2390Arg | missense_variant | 58/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 20, 2015 | The p.Cys2390Arg variant in FBN1 has been identified by our laboratory in 1 adul t with Marfan syndrome and segregated with disease in 2 affected children. It wa s absent from large population studies. A different amino acid change at the sam e position (p.Cys2390Ser) has been reported in one individual with clinical feat ures of Marfan syndrome (Rand-Hendriksen 2007), suggesting that a change at this position may not be tolerated. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. While cysteine subsituti ons are a common finding in individuals with Marfan syndrome (Schrijver 1999), t his variant is not located within the conserved cystein residues of the EGF-like domain. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys2390Arg variant is likely pathogenic. - |
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 31, 2018 | Variant summary: FBN1 c.7168T>C (p.Cys2390Arg) results in a non-conservative amino acid change located in the TB domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant affects a Cysteine, which "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." This variant is not located within the conserved cystein residues of the EGF-like domain, however, cysteine subsitutions are a common finding in individuals with Marfan syndrome (Schrijver 1999) and are listed as one of the criteria for causal FBN1 mutation (Loeys_2010). The variant was absent in 245812 control chromosomes (gnomAD). The variant, c.7168T>C, has not been reported in the literature in individuals affected with Marfan Syndrome but it has been observed in three affected individuals (1 adult with Marfan syndrome and segregated with disease in 2 affected children) tested in another clinical lab. Another variant, c.7168T>A, which affects the same Cysteine, Cys2390Ser has been reported in an affected MFS pt (Rand-Hendrikson_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2019 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys2390 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17663468). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). This variant has been observed in an individual affected with aortic dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 42421). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 2390 of the FBN1 protein (p.Cys2390Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at