ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.8326C>T (p.Arg2776Ter)
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.8326C>T (p.Arg2776Ter)
Variation ID: 16439 Accession: VCV000016439.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48411280 (GRCh38) [ NCBI UCSC ] 15: 48703477 (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 4, 2013 Feb 28, 2024 Oct 26, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.8326C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Arg2776Ter nonsense NC_000015.10:g.48411280G>A NC_000015.9:g.48703477G>A NG_008805.2:g.239509C>T LRG_778:g.239509C>T LRG_778t1:c.8326C>T LRG_778p1:p.Arg2776Ter - Protein change
- R2776*
- Other names
- p.R2776X:CGA>TGA
- Canonical SPDI
- NC_000015.10:48411279:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- variation affecting protein Variation Ontology [VariO:0002]
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
1000 Genomes Project 30x 0.00016
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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 (6) |
criteria provided, multiple submitters, no conflicts
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Aug 10, 2021 | RCV000017901.42 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 12, 2022 | RCV000181630.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 26, 2022 | RCV000631918.14 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2018 | RCV001374806.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2022 | RCV002310993.8 |
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
Help
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
Help
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
(Mar 01, 2021)
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criteria provided, single submitter
Method: research
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Marfan syndrome
Affected status: yes
Allele origin:
unknown
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Centre of Medical Genetics, University of Antwerp
Accession: SCV002025475.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
Comment:
PS4, PS1, PP4 or PS4, PS1, PP1, PP4
Number of individuals with the variant: 4
Sex: female
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Pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000340055.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jul 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown,
paternal
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Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Accession: SCV000930047.1
First in ClinVar: Sep 04, 2019 Last updated: Sep 04, 2019 |
Comment:
At our clinical center The p.R2776* variant was found in one family and one unrelated individual. This variant present in variouas individual studies reported by … (more)
At our clinical center The p.R2776* variant was found in one family and one unrelated individual. This variant present in variouas individual studies reported by other submitters (ClinVar entry - Variation ID:16439), as well as present in population studies (C=0.00001 (1/121406, ExAC)). Functional study of the variant (PMID: 24982166) shows its pathogenic mechanism by linkage of the immature monomers, thus it behaves as a dominant-negative mutation, disrupting not only the mutant protein, but the normal one, which is synthesized from the unchanged allele. (less)
Observation 1:
Clinical Features:
Retinal detachment (present) , High palate (present) , Dental crowding (present) , Micrognathia (present) , Aortic dissection (present) , Arachnodactyly (present) , Flexion contracture (present) … (more)
Retinal detachment (present) , High palate (present) , Dental crowding (present) , Micrognathia (present) , Aortic dissection (present) , Arachnodactyly (present) , Flexion contracture (present) , Striae distensae (present) , Dolichostenomelia (present) , Asymmetric face (present) , Scoliosis (present) (less)
Age: 40-49 years
Sex: male
Method: Bi-directional Sanger sequencing
Observation 2:
Clinical Features:
High palate (present) , Dental crowding (present) , Abnormal dental morphology (present) , Joint hypermobility (present) , Arachnodactyly (present) , Pes planus (present) , Scoliosis … (more)
High palate (present) , Dental crowding (present) , Abnormal dental morphology (present) , Joint hypermobility (present) , Arachnodactyly (present) , Pes planus (present) , Scoliosis (present) , Abnormal sternum morphology (present) , Abnormality of the skin (present) , Narrow nose (present) , High myopia (present) , Dolichostenomelia (present) , Facial asymmetry (present) , Syndactylia (present) (less)
Age: 20-29 years
Sex: female
Observation 3:
Clinical Features:
High palate (present) , Dental crowding (present) , Abnormal dental morphology (present) , Joint hypermobility (present) , Hyperextensible skin (present) , Pes planus (present) , … (more)
High palate (present) , Dental crowding (present) , Abnormal dental morphology (present) , Joint hypermobility (present) , Hyperextensible skin (present) , Pes planus (present) , Aortic aneurysm (present) , Abnormality of the skin (present) (less)
Age: 40-49 years
Sex: male
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Likely pathogenic
(Sep 01, 2018)
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criteria provided, single submitter
Method: research
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Isolated thoracic aortic aneurysm
Affected status: yes
Allele origin:
germline
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Department of Vascular Biology, Beijing Anzhen Hospital
Accession: SCV001439507.1
First in ClinVar: Apr 28, 2021 Last updated: Apr 28, 2021 |
Sex: mixed
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Pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: yes
Allele origin:
unknown
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976751.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PVS1, PP3, PP5
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Pathogenic
(Jan 03, 2022)
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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: SCV000320556.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.R2776* pathogenic mutation (also known as c.8326C>T), located in coding exon 65 of the FBN1 gene, results from a C to T substitution at … (more)
The p.R2776* pathogenic mutation (also known as c.8326C>T), located in coding exon 65 of the FBN1 gene, results from a C to T substitution at nucleotide position 8326. This changes the amino acid from an arginine to a stop codon within coding exon 65. This alteration occurs at the 3' terminus of theFBN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 96 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration, which is also known as p.R1878*, c.5632C>T, has been reported in multiple individuals with Marfan syndrome (Hayward C et al. Hum. Mutat., 1994;3:159-62; Körkkö J et al. J. Med. Genet., 2002 Jan;39:34-41; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Jensen SA et al. Proc Natl Acad Sci U S A, 2014 Jul;111:10155-60; Proost D et al. Hum Mutat, 2015 Aug;36:808-14; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164; Stengl R et al. Orphanet J Rare Dis, 2020 10;15:290). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 12, 2022)
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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: SCV000233933.15
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Functional studies suggest that the variant results in intra-cellular retention of the protein (Jensen et al., 2014); Nonsense variant in the C-terminus predicted to result … (more)
Functional studies suggest that the variant results in intra-cellular retention of the protein (Jensen et al., 2014); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 96 amino acid residues are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and published literature (HGMD; Lonnqvist et al., 1998; Ritty et al., 1999; Jensen et al., 2014); This variant is associated with the following publications: (PMID: 9817919, 10085138, 11826022, 24982166, 7911051, 10756346, 19293843, 33059708, 33824467, 31098894, 9338581, 31730815, 34008892) (less)
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Pathogenic
(Oct 26, 2022)
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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: SCV000753021.7
First in ClinVar: May 28, 2018 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.Leu2854Profs*9, p.Gln2830*, … (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.Leu2854Profs*9, p.Gln2830*, p.Leu2854Profs*9) have been determined to be pathogenic (Invitae). 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: 16439). This premature translational stop signal has been observed in individual(s) with FBN-1 related conditions (PMID: 7911051, 9338581, 11826022). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg2776*) in the FBN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 96 amino acid(s) of the FBN1 protein. (less)
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Pathogenic
(Jan 01, 1994)
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no assertion criteria provided
Method: literature only
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MARFAN SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038180.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a 57-year-old patient with Marfan syndrome (154700) and her 27-year-old son, Hayward et al. (1994) found an arg2776-to-ter mutation predicted to result in premature … (more)
In a 57-year-old patient with Marfan syndrome (154700) and her 27-year-old son, Hayward et al. (1994) found an arg2776-to-ter mutation predicted to result in premature termination of the FBN1 polypeptide chain by 96 amino acids. This mutation was previously designated as ARG1878TER. (less)
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Pathogenic
(Apr 09, 2015)
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no assertion criteria provided
Method: clinical testing
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Marfan's syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052447.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
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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: SCV000787408.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein
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Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Accession: SCV000930047.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvement. | Stengl R | Orphanet journal of rare diseases | 2020 | PMID: 33059708 |
Mutation analysis of the FBN1 gene in a cohort of patients with Marfan Syndrome: A 10-year single center experience. | Mannucci L | Clinica chimica acta; international journal of clinical chemistry | 2020 | PMID: 31730815 |
Application of next-generation sequencing to screen for pathogenic mutations in 123 unrelated Chinese patients with Marfan syndrome or a related disease. | Li J | Science China. Life sciences | 2019 | PMID: 31098894 |
Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. | Proost D | Human mutation | 2015 | PMID: 25907466 |
C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43. | Jensen SA | Proceedings of the National Academy of Sciences of the United States of America | 2014 | PMID: 24982166 |
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 |
Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. | Körkkö J | Journal of medical genetics | 2002 | PMID: 11826022 |
Mutation screening of all 65 exons of the fibrillin-1 gene in 60 patients with Marfan syndrome: report of 12 novel mutations. | Hayward C | Human mutation | 1997 | PMID: 9338581 |
Identification of a novel nonsense mutation in the fibrillin gene (FBN1) using nonisotopic techniques. | Hayward C | Human mutation | 1994 | PMID: 7911051 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FBN1 | - | - | - | - |
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Text-mined citations for rs137854466 ...
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.