15-48420764-C-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000138.5(FBN1):c.7742G>A(p.Cys2581Tyr) 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. C2581F) 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.7742G>A | p.Cys2581Tyr | missense_variant | 63/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.7742G>A | p.Cys2581Tyr | missense_variant | 62/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.7742G>A | p.Cys2581Tyr | missense_variant | 63/66 | 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 | - - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 30, 2016 | The p.C2581Y variant (also known as c.7742G>A), located in coding exon 62 of the FBN1 gene, results from a G to A substitution at nucleotide position 7742. The cysteine at codon 2581 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with some symptoms of Marfan syndrome; however, limited clinical information was available (Howarth R et al. Genet. Test., 2007;11:146-52; Turner CL et al. Am. J. Med. Genet. A, 2009 Feb;149A:161-70). Several alternate amino acid substitutions at this position have been reported in individuals with Marfan syndrome, including a reported de novo case with p.C2581S, suggesting this position to be a mutation hotspot (Loeys B et al. Arch. Intern. Med., 2001 Nov;161:2447-54; Hilhorst-Hofstee Y et al. J. Child Neurol., 2008 Aug;23:954-5; Körkkö J et al. J. Med. Genet., 2002 Jan;39:34-41; ). This amino acid is located in a calcium-binding EGF-like (cbEGF) domain, and is predicted to participate in disulfide bonding. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at