rs111687884
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000138.5(FBN1):c.643C>T(p.Arg215Ter) variant causes a stop gained 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R215R) has been classified as Likely benign. 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.643C>T | p.Arg215Ter | stop_gained | 7/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.643C>T | p.Arg215Ter | stop_gained | 6/65 | ||
FBN1 | NM_001406717.1 | c.643C>T | p.Arg215Ter | stop_gained | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.643C>T | p.Arg215Ter | stop_gained | 7/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.643C>T | p.Arg215Ter | stop_gained, NMD_transcript_variant | 7/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.643C>T | p.Arg215Ter | stop_gained, NMD_transcript_variant | 7/68 | ||||
FBN1 | ENST00000537463.6 | c.636+7C>T | splice_region_variant, intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 01, 2011 | The Arg215X variant has been reported in the literature in one individual with c linical features of Marfan syndrome (Matsukawa 2001). This variant leads to a pr emature stop codon at position 215, which is predicted to lead to a truncated or absent protein. Therefore, this variant is highly likely to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Nov 03, 2022 | The c.643C>T;p.(Arg215*) variant creates a premature translational stop signal in the FBN1 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 42401; PMID: 11139245; 16220557; 17657824; 27611364; 32431097) - PS4. This variant is not present in population databases (rs111687884, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 06, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 25525159, 11139245, 31098894, 29357934, 32431097, 17657824, 19293843, 27234404, 27611364, 16220557, AgaogluNB2022, 15241795) - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 24, 2017 | - - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2015 | The p.R215* pathogenic mutation (also known as c.643C>T), located in coding exon 6 of the FBN1 gene in the hybrid #01 domain, results from a C to T substitution at nucleotide position 643. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation was originally reported in a 57-year-old male Japanese patient with a severe phenotype of ocular, skeletal, and cardiovascular features and positive family history. He had an acute aortic dissection at 38 years of age and also had annulo-aortic ectasia and aortic regurgitation (Matsukawa R et al. Hum Mutat. 2001;17(1):71-2). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change creates a premature translational stop signal (p.Arg215*) 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 variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 11139245, 16220557, 17657824, 27611364). ClinVar contains an entry for this variant (Variation ID: 42401). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at