ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.8525_8529del (p.Leu2842fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000138.5(FBN1):c.8525_8529del (p.Leu2842fs)
Variation ID: 419823 Accession: VCV000419823.13
- Type and length
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Deletion, 5 bp
- Location
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Cytogenetic: 15q21.1 15: 48411077-48411081 (GRCh38) [ NCBI UCSC ] 15: 48703274-48703278 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 27, 2017 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.8525_8529del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Leu2842fs frameshift NM_000138.4:c.8525_8529delTTAAC NC_000015.10:g.48411080_48411084del NC_000015.9:g.48703277_48703281del NG_008805.2:g.239708_239712del LRG_778:g.239708_239712del LRG_778t1:c.8525_8529del - Protein change
- L2842fs
- Other names
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- Canonical SPDI
- NC_000015.10:48411076:GTTAAGTT:GTT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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FBN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7137 | 7452 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Jun 12, 2023 | RCV000485375.5 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2024 | RCV000659590.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2023 | RCV001063776.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 19, 2020 | RCV001264508.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 4, 2019 | RCV002446924.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781429.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Pathogenic
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442698.1
First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020 |
Comment:
Variant summary: FBN1 c.8525_8529delTTAAC (p.Leu2842ProfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: FBN1 c.8525_8529delTTAAC (p.Leu2842ProfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar database. The variant was absent in 251280 control chromosomes (gnomAD and publication data). c.8525_8529delTTAAC has been reported in the literature in individuals affected with Marfan Syndrome (Paiz_2000, Hung_2009, Magyar_2009, Aalberts_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and uncertain significance (1x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002679158.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.8525_8529delTTAAC pathogenic mutation, located in coding exon 65 of the FBN1 gene, results from a deletion of 5 nucleotides at nucleotide positions 8525 to … (more)
The c.8525_8529delTTAAC pathogenic mutation, located in coding exon 65 of the FBN1 gene, results from a deletion of 5 nucleotides at nucleotide positions 8525 to 8529, causing a translational frameshift with a predicted alternate stop codon (p.L2842Pfs*7). This mutation has been reported in multiple individuals with Marfan syndrome (Palz M et al. Am. J. Med. Genet., 2000 Mar;91:212-21; Rommel K et al. Hum. Mutat., 2005 Dec;26:529-39; Hung CC et al. Ann. Hum. Genet., 2009 Nov;73:559-67; Magyar I et al. Hum. Mutat., 2009 Sep;30:1355-64). 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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000567922.3
First in ClinVar: Apr 27, 2017 Last updated: Jun 24, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 30 amino acids are … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 30 amino acids are replaced with 6 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 16220557, 19618372, 19839986, 10756346, 32679894, 33910934, 27611364, 24161884, 31098894, 12938084) (less)
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Pathogenic
(May 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Familial thoracic aortic aneurysm and aortic dissection
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001228637.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FBN1 protein in which other variant(s) (p.Gln2867*) have … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FBN1 protein in which other variant(s) (p.Gln2867*) have been determined to be pathogenic (PMID: 19293843). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 419823). This premature translational stop signal has been observed in individual(s) with clinical features of FBN1-related conditions (PMID: 10756346, 19618372, 27611364). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu2842Profs*7) in the FBN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the FBN1 protein. (less)
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Likely pathogenic
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810264.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Uncertain significance
(Nov 07, 2017)
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no assertion criteria provided
Method: clinical testing
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Marfan syndrome
Affected status: yes
Allele origin:
germline
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Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000787422.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genetic testing of 248 Chinese aortopathy patients using a panel assay. | Yang H | Scientific reports | 2016 | PMID: 27611364 |
Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome. | Aalberts JJ | Gene | 2014 | PMID: 24161884 |
Identification of a novel lethal fibrillin-1 gene mutation in a Chinese Marfan family and correlation of 3' fibrillin-1 gene mutations with phenotype. | Gao LG | Chinese medical journal | 2010 | PMID: 21034599 |
Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. | Hung CC | Annals of human genetics | 2009 | PMID: 19839986 |
Quantitative sequence analysis of FBN1 premature termination codons provides evidence for incomplete NMD in leukocytes. | Magyar I | Human mutation | 2009 | PMID: 19618372 |
Identification of fibrillin-1 gene mutations in Marfan syndrome by high-resolution melting analysis. | Hung CC | Analytical biochemistry | 2009 | PMID: 19328768 |
Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. | Stheneur C | European journal of human genetics : EJHG | 2009 | PMID: 19293843 |
Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome. | Rommel K | Human mutation | 2005 | PMID: 16220557 |
Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. | Collod-Béroud G | Human mutation | 2003 | PMID: 12938084 |
Clustering of mutations associated with mild Marfan-like phenotypes in the 3' region of FBN1 suggests a potential genotype-phenotype correlation. | Palz M | American journal of medical genetics | 2000 | PMID: 10756346 |
Text-mined citations for rs1064794130 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.