rs1555395663
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000138.5(FBN1):c.5930G>A(p.Cys1977Tyr) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1977S) 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 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.5930G>A | p.Cys1977Tyr | missense_variant | 49/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.5930G>A | p.Cys1977Tyr | missense_variant | 48/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.5930G>A | p.Cys1977Tyr | missense_variant | 49/66 | 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, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 22, 2021 | This sequence change replaces cysteine with tyrosine at codon 1977 of the FBN1 protein (p.Cys1977Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. For these reasons, this variant has been classified as Pathogenic. Two additional missense substitutions at this codon (p.Cys1977Arg, p.Cys1977Trp) have been reported in individuals affected with Marfan syndrome (PMID: 12161601, 18435798). This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 10486319, 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Experimental studies indicate that this missense change causes EGF-l intradomain misfolding (PMID: 15371449). This variant has been reported in individuals affected with Marfan syndrome (PMID: 9399842, 15241795). ClinVar contains an entry for this variant (Variation ID: 527152). This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at