ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.8080C>T (p.Arg2694Ter)
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
-
NM_000138.5(FBN1):c.8080C>T (p.Arg2694Ter)
Variation ID: 163461 Accession: VCV000163461.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q21.1 15: 48412715 (GRCh38) [ NCBI UCSC ] 15: 48704912 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 2, 2015 Feb 28, 2024 Sep 28, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000138.5:c.8080C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Arg2694Ter nonsense NC_000015.10:g.48412715G>A NC_000015.9:g.48704912G>A NG_008805.2:g.238074C>T LRG_778:g.238074C>T LRG_778t1:c.8080C>T LRG_778p1:p.Arg2694Ter - Protein change
- R2694*
- Other names
- p.R2694X:CGA>TGA
- NM_000138.5(FBN1):c.8080C>T
- p.Arg2694Ter
- Canonical SPDI
- NC_000015.10:48412714:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
FBN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7116 | 7430 |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (5) |
reviewed by expert panel
|
Sep 28, 2023 | RCV000150695.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Feb 4, 2022 | RCV000181617.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 25, 2023 | RCV000529472.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 12, 2018 | RCV001002020.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 21, 2022 | RCV002415636.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 16, 2019 | RCV001192914.3 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Sep 28, 2023)
|
reviewed by expert panel
Method: curation
|
Marfan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen FBN1 Variant Curation Expert Panel, ClinGen
Accession: SCV004037331.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
The NM_00138 c.8080C>T, is a nonsense variant in FBN1 which is predicted to result in a premature stop codon at position 2694, and likely results … (more)
The NM_00138 c.8080C>T, is a nonsense variant in FBN1 which is predicted to result in a premature stop codon at position 2694, and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with thoracic aortic aneurysm, ectopia lentis, and a systemic score of 10, which is a highly specific phenotype for Marfan syndrome (internal data) (PP4). The variant has been identified as a de novo occurrence, without confirmation of paternity and maternity, in one individual with highly specific phenotype and in one individual with a phenotype consistent with the gene but not highly specific (Internal data- Bichat) (PM6). This variant was also found in a proband with ectopia lentis, thoraic aortic aneurysm, and skeletal features, and was found to segregate with the disease in 1 affected family member (internal data, John Hopkins). This variant has been reported 9 times in ClinVaras pathogenic (Variation ID: 163461). At least 20 other probands with a clinical diagnosis of Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (PMID 17680538, 19293843, 19839986, 24199744, 26787436, 14695540, 18435798, 26133393, internal data, PS4). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PS4, PM6, PM2_Sup, PP4. (less)
|
|
Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Marfan syndrome
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781423.1
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
|
|
Pathogenic
(Aug 07, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Marfan syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198056.4
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Comment:
The Arg2694X variant in FBN1 has been reported in at least 10 individuals with s uspected or confirmed Marfan syndrome (Biggin 2004, Chen 2007, Attanasio … (more)
The Arg2694X variant in FBN1 has been reported in at least 10 individuals with s uspected or confirmed Marfan syndrome (Biggin 2004, Chen 2007, Attanasio 2008, S theneur 2009, Hung 2009). It was absent from large population studies. This non sense variant leads to a premature termination codon at position 2694, which is predicted to lead to a truncated or absent protein. Heterozygous loss of functio n of the FBN1 gene is an established disease mechanism in Marfan syndrome. In su mmary, this variant meets our criteria to be classified as pathogenic (http://pc pgm.partners.org/LMM). (less)
Number of individuals with the variant: 2
|
|
Pathogenic
(Aug 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001159839.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The FBN1 c.8080C>T; p.Arg2694Ter variant (rs193922108) is reported in the literature in multiple individuals affected with Marfan syndrome (Attanasio 2008, Biggin 2004, Chen 2007, Hung … (more)
The FBN1 c.8080C>T; p.Arg2694Ter variant (rs193922108) is reported in the literature in multiple individuals affected with Marfan syndrome (Attanasio 2008, Biggin 2004, Chen 2007, Hung 2009, Stheneur 2009). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 163461). It is found on one chromosome in the Exome Variant Server but is otherwise absent from general population databases (1000 Genomes Project and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Nonsense variants in FBN1 meet the revised Ghent nosology criteria for classification as pathogenic (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Attanasio M et al. FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Clin Genet. 2008 Jul;74(1):39-46. Biggin A et al. Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat. 2004 Jan;23(1):99. Chen XJ et al. Two gene mutations in fibrillin 1 of Marfan syndrome. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007 Aug;24(4):440-2. Hung CC et al. Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. Ann Hum Genet. 2009 Nov;73(Pt 6):559-67. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. (less)
|
|
Pathogenic
(Dec 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361372.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: FBN1 c.8080C>T (p.Arg2694X) 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.8080C>T (p.Arg2694X) 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 by our laboratory. The variant was absent in 251382 control chromosomes (gnomAD). c.8080C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (Franken_206, Attanasio_2008, Biggin_2004, Hung_2009, Pees_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Mar 01, 2021)
|
criteria provided, single submitter
Method: research
|
Marfan syndrome
Affected status: yes
Allele origin:
unknown
|
Centre of Medical Genetics, University of Antwerp
Accession: SCV002025473.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
Comment:
PM2, PVS1, PP4
Sex: male
|
|
Pathogenic
(Oct 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002679066.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R2694* pathogenic mutation (also known as c.8080C>T), located in coding exon 64 of the FBN1 gene, results from a C to T substitution at … (more)
The p.R2694* pathogenic mutation (also known as c.8080C>T), located in coding exon 64 of the FBN1 gene, results from a C to T substitution at nucleotide position 8080. This changes the amino acid from an arginine to a stop codon within coding exon 64. This variant has been detected in several unrelated individuals with Marfan syndrome (MFS) or features consistent with MFS (Biggin A et al. Hum Mutat, 2004 Jan;23:99; Attanasio M et al. Clin Genet, 2008 Jul;74:39-46; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Hung CC et al. Ann Hum Genet, 2009 Nov;73:559-67; Pees C et al. Clin Genet, 2014 Dec;86:552-7; Franken R et al. Eur Heart J, 2016 Nov;37:3285-3290; Zarate YA et al. Genet Med, 2016 Apr;18:356-63; Wu Y et al. Biosci Rep, 2020 12;40). 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. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Feb 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000233920.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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: 22913777, 24941995, 16061422, 19293843, 17680538, 18435798, 14695540, 26787436, 19839986, 25525159, 24199744, 26133393, 31536524) (less)
|
|
Pathogenic
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Invitae
Accession: SCV000628006.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 163461). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 163461). This premature translational stop signal has been observed in individual(s) with Marfan syndrome (PMID: 14695540, 17680538, 18435798, 19293843, 19839986, 26787436). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2694*) 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). (less)
|
|
Pathogenic
(Nov 07, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Marfan syndrome
Affected status: yes
Allele origin:
germline
|
Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000787396.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
|
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 |
---|---|---|---|---|
Marfan syndrome: whole-exome sequencing reveals de novo mutations, second gene and genotype-phenotype correlations in the Chinese population. | Wu Y | Bioscience reports | 2020 | PMID: 33200202 |
Genotype impacts survival in Marfan syndrome. | Franken R | European heart journal | 2016 | PMID: 26787436 |
Aortic dilation, genetic testing, and associated diagnoses. | Zarate YA | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26133393 |
Detection of 15 novel mutations in 52 children from 40 families with the Marfan or Loeys-Dietz syndrome and phenotype-genotype correlations. | Pees C | Clinical genetics | 2014 | PMID: 24199744 |
Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. | Hung CC | Annals of human genetics | 2009 | PMID: 19839986 |
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 |
FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. | Attanasio M | Clinical genetics | 2008 | PMID: 18435798 |
[Two gene mutations in fibrillin 1 of Marfan syndrome]. | Chen XJ | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2007 | PMID: 17680538 |
The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. | Comeglio P | Human mutation | 2007 | PMID: 17657824 |
Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. | Biggin A | Human mutation | 2004 | PMID: 14695540 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/83c08467-6b08-4c83-98b3-504c8959129d | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs200309328 ...
HelpRecord last updated Mar 05, 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.