chr15-48503917-G-C
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000138.5(FBN1):c.1983C>G(p.Cys661Trp) variant causes a missense change involving the alteration of a non-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. C661Y) 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.1983C>G | p.Cys661Trp | missense_variant | 17/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.1983C>G | p.Cys661Trp | missense_variant | 16/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.1983C>G | p.Cys661Trp | missense_variant | 17/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 26, 2017 | This variant affects a cysteine residue located within a hybrid motif domain of the FBN1 protein. Cysteine residues in these domains 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 within the hybrid motif domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic. Three other different missense substitutions at this codon (p.Cys661Tyr, p.Cys661Gly, p.Cys661Arg) have been reported in individuals affected with Marfan syndrome or fibrillinopathies (PMID: 12203987, 19293843, 9016526). This suggests that the cysteine residue is critical for FBN1 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been reported in one individual affected with Marfan syndrome in the Universal Mutation Database (PMID: 10612827). This sequence change replaces cysteine with tryptophan at codon 661 of the FBN1 protein (p.Cys661Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at