ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.4467T>A (p.Asn1489Lys)
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.4467T>A (p.Asn1489Lys)
Variation ID: 36076 Accession: VCV000036076.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48468527 (GRCh38) [ NCBI UCSC ] 15: 48760724 (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 Jan 31, 2015 May 1, 2024 Sep 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.4467T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Asn1489Lys missense NC_000015.10:g.48468527A>T NC_000015.9:g.48760724A>T NG_008805.2:g.182262T>A LRG_778:g.182262T>A LRG_778t1:c.4467T>A LRG_778p1:p.Asn1489Lys - Protein change
- N1489K
- Other names
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- Canonical SPDI
- NC_000015.10:48468526:A:T
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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 |
7456 | 7786 |
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
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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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Likely pathogenic (2) |
criteria provided, single submitter
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Mar 1, 2021 | RCV000029738.15 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Oct 20, 2022 | RCV000586485.15 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jan 20, 2016 | RCV000755191.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 22, 2023 | RCV000855643.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 6, 2023 | RCV001046640.13 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2023 | RCV001843461.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 28, 2016 | RCV002326690.9 |
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
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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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Likely 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: SCV002025320.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
Comment:
PM2, PS1, PP4
Sex: female
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Likely pathogenic
(May 22, 2023)
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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: SCV000695543.4
First in ClinVar: Mar 17, 2018 Last updated: Jun 24, 2023 |
Comment:
Variant summary: FBN1 c.4467T>A (p.Asn1489Lys) results in a non-conservative amino acid change located in the EGF-like calcium-binding and EGF-like domains of the encoded protein sequence. … (more)
Variant summary: FBN1 c.4467T>A (p.Asn1489Lys) results in a non-conservative amino acid change located in the EGF-like calcium-binding and EGF-like domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251118 control chromosomes. c.4467T>A has been reported in the literature in individuals affected with Marfan Syndrome (examples- Baetens_2011, Regalado_2016). 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. The following publications have been ascertained in the context of this evaluation (PMID: 21542060, 20082464, 24793577, 25907466, 26621581, 30371227, 35058154). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 . Multiple laboratories reported the variant with conflicting assessments: Pathogenic (n=1), Likely Pathogenic (n=4) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Feb 14, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564426.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The FBN1 c.4467T>A; p.Asn1489Lys variant (rs193922205) is reported in individuals with features of Marfan syndrome (Baetens 2011, Brautbar 2010) and is reported to segregate with … (more)
The FBN1 c.4467T>A; p.Asn1489Lys variant (rs193922205) is reported in individuals with features of Marfan syndrome (Baetens 2011, Brautbar 2010) and is reported to segregate with thoracic aortic aneurysms and dissections (TAAD) in three affected individuals of a family (Regalado 2016). This variant is reported in ClinVar (Variation ID: 36076). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.693). The asparagine at codon 1489 is a well conserved residue of the EGF consensus sequence and is critical for calcium binding (Wu 1995). Based on available information, this variant is considered to be likely pathogenic. References: Baetens M et al. Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat. 2011 Sep;32(9):1053-62. PMID: 21542060. Brautbar A et al. FBN1 mutations in patients with descending thoracic aortic dissections. Am J Med Genet A. 2010 Feb;152A(2):413-6. PMID: 20082464. Regalado ES et al. FBN1 variants in familial thoracic aortic aneurysms and dissections. Clin Genet. 2016 Jun;89(6):719-23. PMID: 26621581. Wu YS et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem Biol. 1995 Feb;2(2):91-7. PMID: 9383409. (less)
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Likely pathogenic
(Sep 19, 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: SCV002102630.3
First in ClinVar: Mar 12, 2022 Last updated: Sep 30, 2023 |
Comment:
Reported to segregate with aortic aneurysm and/or aortic dissection in three members from a single family without a clinical diagnosis of Marfan syndrome (Regalado et … (more)
Reported to segregate with aortic aneurysm and/or aortic dissection in three members from a single family without a clinical diagnosis of Marfan syndrome (Regalado et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24793577, 30371227, 25907466, 20082464, 26621581, 21542060, 20591885, 35058154) (less)
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Pathogenic
(Apr 06, 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: SCV001210551.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 36076). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 20082464, 21542060, 26621581; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1489 of the FBN1 protein (p.Asn1489Lys). (less)
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Likely pathogenic
(Oct 28, 2016)
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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: SCV002638901.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.N1489K variant (also known as c.4467T>A), located in coding exon 36 of the FBN1 gene, results from a T to A substitution at nucleotide … (more)
The p.N1489K variant (also known as c.4467T>A), located in coding exon 36 of the FBN1 gene, results from a T to A substitution at nucleotide position 4467. The asparagine at codon 1489 is replaced by lysine, an amino acid with some similar properties. This variant was described in a patient reported to have a diagnosis of Marfan syndrome (MFS) (Baetens M et al. Hum Mutat. 2011;32(9):1053-62). It was also reported in a patient with primary descending thoracic aortic dissection who did not fulfill clinical criteria for MFS (Brautbar A et al. Am J Med Genet A. 2010;152A(2):413-6). In another family, this alteration was identified three individuals reported to have aortic aneurysm or dissection (Regalado ES at al. Clin Genet. 2016;89(6):719-23). This variant was previously reported in the SNPDatabase as rs193922205. It was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), Exome Aggregation Consortium (ExAC) and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Jan 20, 2016)
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no assertion criteria provided
Method: research
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Familial thoracic aortic aneurysms
Acute aortic dissections
Affected status: yes
Allele origin:
unknown
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000883020.1
First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 2019 |
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Uncertain significance
(Nov 07, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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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: SCV000787068.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
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Uncertain significance
(Feb 11, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not specified
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000058845.6
First in ClinVar: May 03, 2013 Last updated: Nov 08, 2019 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort. | Meester JAN | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 35058154 |
Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease. | Mariscalco G | Journal of the American Heart Association | 2018 | PMID: 30371227 |
Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections. | Regalado ES | Clinical genetics | 2016 | PMID: 26621581 |
Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. | Proost D | Human mutation | 2015 | PMID: 25907466 |
The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). | Lerner-Ellis JP | Molecular genetics and metabolism | 2014 | PMID: 24793577 |
Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. | Baetens M | Human mutation | 2011 | PMID: 21542060 |
FBN1 mutations in patients with descending thoracic aortic dissections. | Brautbar A | American journal of medical genetics. Part A | 2010 | PMID: 20082464 |
Text-mined citations for rs193922205 ...
HelpRecord last updated May 12, 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.