rs794728187
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_ModeratePM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000138.5(FBN1):c.2201G>T(p.Cys734Phe) 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C734Y) 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 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.2201G>T | p.Cys734Phe | missense_variant | 19/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.2201G>T | p.Cys734Phe | missense_variant | 18/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.2201G>T | p.Cys734Phe | missense_variant | 19/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2014 | p.Cys734Phe (TGC>TTC): c.2201 G>T in exon 19 of the FBN1 gene (NM_000138.4)The C734F mutation in the FBN1 gene has been reported previously in a patient with Marfan syndrome, however no segregation or population data were reported (Katzke S et al., 2002). In addition, the C734F mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Moreover, C734F results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is completely conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, mutations in nearby residues (E726G, C727Y, G737V, C739R) have been reported in association with Marfan syndrome and ectopia lentis, further supporting the functional importance of this region of the protein.In summary, C734F in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at