rs397515818
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000138.5(FBN1):c.497G>C(p.Cys166Ser) 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. C166F) 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.497G>C | p.Cys166Ser | missense_variant | 6/66 | ENST00000316623.10 | NP_000129.3 | |
FBN1 | NM_001406716.1 | c.497G>C | p.Cys166Ser | missense_variant | 5/65 | NP_001393645.1 | ||
FBN1 | NM_001406717.1 | c.497G>C | p.Cys166Ser | missense_variant | 6/9 | NP_001393646.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.497G>C | p.Cys166Ser | missense_variant | 6/66 | 1 | NM_000138.5 | ENSP00000325527 | P1 | |
FBN1 | ENST00000559133.6 | c.497G>C | p.Cys166Ser | missense_variant, NMD_transcript_variant | 6/67 | 1 | ENSP00000453958 | |||
FBN1 | ENST00000674301.2 | c.497G>C | p.Cys166Ser | missense_variant, NMD_transcript_variant | 6/68 | ENSP00000501333 | ||||
FBN1 | ENST00000537463.6 | c.497G>C | p.Cys166Ser | missense_variant, NMD_transcript_variant | 6/31 | 5 | ENSP00000440294 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
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 | Apr 17, 2012 | The Cys166Ser variant (FBN1) has been reported in one individual with clinical f eatures of Marfan syndrome (Biggin 2004). In addition, functional analysis revea ls that the variant affects normal fibrillin microfibril assembly (Massan-Wu 201 0). Furthermore, this variant alters a conserved cysteine residue which is predi cted to disrupt a disulfide bridge in an EGF-like domain of the protein. Cystein e residue alterations in EGF-like domains of FBN1 are commonly altered in patien ts with clinical features of Marfan syndrome (Schrijver 1999). In summary, this variant is likely to be pathogenic, though segregation studies and functional an alyses are required to fully establish the pathogenicity of this variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at