rs397515767
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.239G>A(p.Cys80Tyr) 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. 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. C80G) 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.239G>A | p.Cys80Tyr | missense_variant | 3/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.239G>A | p.Cys80Tyr | missense_variant | 2/65 | ||
FBN1 | NM_001406717.1 | c.239G>A | p.Cys80Tyr | missense_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.239G>A | p.Cys80Tyr | missense_variant | 3/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.239G>A | p.Cys80Tyr | missense_variant, NMD_transcript_variant | 3/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.239G>A | p.Cys80Tyr | missense_variant, NMD_transcript_variant | 3/68 | ||||
FBN1 | ENST00000537463.6 | c.239G>A | p.Cys80Tyr | missense_variant, NMD_transcript_variant | 3/31 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 17, 2008 | - - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 17, 2018 | The p.C80Y variant (also known as c.239G>A), located in coding exon 2 of the FBN1 gene, results from a G to A substitution at nucleotide position 239. The cysteine at codon 80 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the 4-cysteine motif. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This particular cysteine alteration has been reported in a Marfan syndrome (MFS) cohort and has been shown to segregate with disease in a family with incomplete MFS (Howarth R et al. Genet. Test. 2007;11:146-52; LeBlanc SK et al. J AAPOS. 2014;18:90-2). Two likely pathogenic alterations, p.C80R and p.C80G, have been described in the same codon (Stheneur C et al. Eur. J. Hum. Genet. 2009;17:1121-8; Baetens M et al. Hum. Mutat. 2011;32:1053-62). 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
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 14, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys80 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19161152, 19293843, 21542060), which suggests that this may be a clinically significant amino acid residue. 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 42302). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 17627385, 19161152). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 80 of the FBN1 protein (p.Cys80Tyr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at