rs140583
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000138.5(FBN1):c.2581C>T(p.Arg861Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000138.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.2581C>T | p.Arg861Ter | stop_gained | 22/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.2581C>T | p.Arg861Ter | stop_gained | 21/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.2581C>T | p.Arg861Ter | stop_gained | 22/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461812Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727212
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Centre of Medical Genetics, University of Antwerp | Mar 01, 2021 | PM2, PVS1, PP4 - |
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:2
Pathogenic, no assertion criteria provided | research | Centre for Genomic and Experimental Medicine, University of Edinburgh | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2018 | The p.R861* pathogenic mutation (also known as c.2581C>T), located in coding exon 21 of the FBN1 gene, results from a C to T substitution at nucleotide position 2581. This changes the amino acid from an arginine to a stop codon within coding exon 21. This alteration has been reported in multiple individuals with Marfan syndrome (MFS) or MFS-related phenotypes (Liu WO et al. Genet Test. 1997-1998;1(4):237-42; Schrijver I et al. Am J Hum Genet. 2002;71(2):223-37; Arbustini E et al. Hum Mutat. 2005;26(5):494; Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8; Katzke S et al. Hum Mutat 2002; 20(3):197-208; Magyar I et al. Hum Mutat. 2009;30(9):1355-64; Guo J et al. Sci Rep. 2015;5:13115). One study of patient-derived induced pluripotent stem cells exhibiting this mutation reported impact to microfibril formation, osteogenesis, contractility, and calcium influx, with rescue of some defects in mutation-corrected cells (Park JW et al. Int J Biol Sci. 2017;13(5):588-603). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 25, 2016 | - - |
Isolated thoracic aortic aneurysm Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Department of Vascular Biology, Beijing Anzhen Hospital | Sep 01, 2018 | - - |
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 20, 2017 | Variant summary: The FBN1 c.2581C>T (p.Arg861X) variant results in a premature termination codon, predicted to cause a truncated or absent FBN1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 121196 control chromosomes (ExAC). Multiple publications cite the variant in affected individuals, along with multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2021 | Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies using induced pluripotent stem cells demonstrated that this variant decreases FBN1 protein expression, impairs osteogenesis, reduces contractility and alters calcium signaling in derivative mesenchymal stem cells and/or vascular smooth muscle cells (Park et al., 2017); Reported in ClinVar as pathogenic (ClinVar Variant ID# 265401; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 26272055, 29357934, 29543232, 10464652, 12203992, 12068374, 19293843, 22005308, 19618372, 19533785, 16222657, 17657824, 28539832) - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg861*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This premature translational stop signal has been observed in individual(s) with Marfan syndrome, clinical features consistent with Marfan syndrome, or thoracic aortic aneurysm and dissection and Marfan syndrome (PMID: 2005308, 10464652, 16222657, 17657824, 19293843, 26272055). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265401). For these reasons, this variant has been classified as Pathogenic. - |
Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Nov 19, 2021 | FBN1 NM_000138.4 exon 22 p.Arg861* (c.2581C>T): This variant has been reported in the literature in several individuals with features or a clinical diagnosis of Marfan syndrome, including at least 1 individual as de novo (Katzke 2002 PMID:12203992, Schrijver 2002 PMID:12068374, Arbustini 2005 PMID:16222657, Comeglio 2007 PMID:17657824, Chung 2009 PMID:19533785, Magyar 2009 PMID:19618372, Stheneur 2009 PMID:19293843, Guo 2015 PMID:26272055). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:265401). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Dietz 2017 PMID: 20301510). In summary, this variant is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at