rs112550005
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000138.5(FBN1):c.7240C>T(p.Arg2414Ter) variant causes a stop gained change. 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
FBN1
NM_000138.5 stop_gained
NM_000138.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.59
Genes affected
FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-48425829-G-A is Pathogenic according to our data. Variant chr15-48425829-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 519729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48425829-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FBN1 | NM_000138.5 | c.7240C>T | p.Arg2414Ter | stop_gained | 59/66 | ENST00000316623.10 | NP_000129.3 | |
| FBN1 | NM_001406716.1 | c.7240C>T | p.Arg2414Ter | stop_gained | 58/65 | NP_001393645.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FBN1 | ENST00000316623.10 | c.7240C>T | p.Arg2414Ter | stop_gained | 59/66 | 1 | NM_000138.5 | ENSP00000325527 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Marfan syndrome Pathogenic:7
| 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 | Baylor Genetics | Jun 03, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Aug 26, 2019 | The p.Arg2414Ter variant is a known mutation associated with MFS (PMID: 12068374, 19618372). This variant is absent from large population studies (ExAC no frequency). ClinVar has an entry for this variant (Variation ID: 519729). LoF variants in FBN1 gene are a known disease-cause mutations (ExAC pLI = 1.00)(PMID: 20591885). - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Nov 03, 2022 | The c.7240C>T;p.(Arg2414*) 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: 519729; PMID: 34122512; 30542390; 19618372; 12068374; 21907952; 11826022) - PS4. This variant is not present in population databases (rs112550005, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 29, 2024 | - - |
| Pathogenic, criteria provided, single submitter | research | Centre of Medical Genetics, University of Antwerp | Mar 01, 2021 | PM2, PVS1, PP1, PP4 or PM2, PVS1, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals with Marfan syndrome and as pathogenic by multiple clinical testing laboratories (ClinVar, PMID: 32679894). (SP) 1206 - This variant has been shown to be paternally inherited (external clinical testing laboratory). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 16, 2024 | The p.R2414* pathogenic mutation (also known as c.7240C>T), located in coding exon 58 of the FBN1 gene, results from a C to T substitution at nucleotide position 7240. This changes the amino acid from an arginine to a stop codon within coding exon 58. This alteration has been reported in multiple individuals with Marfan syndrome (MFS) or MFS-related phenotypes (Körkkö J et al. J. Med. Genet. 2002 Jan;39:34-41, Schrijver I et al. Am. J. Hum. Genet. 2002 Aug;71:223-37, Magyar I et al. Hum. Mutat. 2009 Sep;30:1355-64, Ogawa N et al. Am. J. Cardiol. 2011 Dec;108:1801-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 15, 2016 | - - |
FBN1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 17, 2024 | The FBN1 c.7240C>T variant is predicted to result in premature protein termination (p.Arg2414*). This variant has been reported in several individuals with Marfan syndrome (see examples: Table 5, Körkkö et al. 2002. PubMed ID: 11826022; Table S3, Chen et al. 2021. PubMed ID: 34550612; Table S1, Meester et al. 2022. PubMed ID: 35058154; Magyar et al. 2009. PubMed ID: 19618372; Abuduxikuer and Wang. 2021. PubMed ID: 34122512; Table S2, Proost et al. 2015. PubMed ID: 25907466). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in FBN1 are expected to be pathogenic, and this variant has been consistently interpreted as pathogenic by other laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/519729/). This variant is interpreted as pathogenic. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 04, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 519729). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 11826022, 27112580). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2414*) 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at