rs886039066
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.1129T>C(p.Cys377Arg) 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. C377Y) 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 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.1129T>C | p.Cys377Arg | missense_variant | 10/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.1129T>C | p.Cys377Arg | missense_variant | 9/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.1129T>C | p.Cys377Arg | missense_variant | 10/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.1129T>C | p.Cys377Arg | missense_variant, NMD_transcript_variant | 10/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.1129T>C | p.Cys377Arg | missense_variant, NMD_transcript_variant | 10/68 | ||||
FBN1 | ENST00000537463.6 | c.636+17034T>C | intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2017 | The p.C377R variant (also known as c.1129T>C), located in coding exon 9 of the FBN1 gene, results from a T to C substitution at nucleotide position 1129. The cysteine at codon 377 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in TB domain 2. Based on internal structural assessment, this alteration results in the loss of a structurally stabilizing disulfide bond in TB domain 2 (Yuan X et al. EMBO J. 1997;16(22):6659-66). 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;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2018 | 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). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 264158). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 377 of the FBN1 protein (p.Cys377Arg). 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