ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.6806T>C (p.Ile2269Thr)
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.6806T>C (p.Ile2269Thr)
Variation ID: 36107 Accession: VCV000036107.79
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48430736 (GRCh38) [ NCBI UCSC ] 15: 48722933 (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 May 29, 2016 May 12, 2024 Nov 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.6806T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Ile2269Thr missense NC_000015.10:g.48430736A>G NC_000015.9:g.48722933A>G NG_008805.2:g.220053T>C LRG_778:g.220053T>C LRG_778t1:c.6806T>C LRG_778p1:p.Ile2269Thr - Protein change
- I2269T
- Other names
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- Canonical SPDI
- NC_000015.10:48430735:A:G
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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 |
7458 | 7789 |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2021 | RCV000029769.18 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 29, 2023 | RCV000255307.33 | |
Pathogenic (1) |
criteria provided, single submitter
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May 18, 2017 | RCV000515227.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2017 | RCV000586646.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 2, 2023 | RCV000534047.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2021 | RCV002310995.9 |
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
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
(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: SCV000781404.1
First in ClinVar: Apr 21, 2018 Last updated: Apr 21, 2018 |
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Likely pathogenic
(May 04, 2018)
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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: SCV000603655.2
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The c.6806T>C; p.Ile2269Thr variant (rs193922228) has been reported in multiple individuals affected with Marfan syndrome or FBN1-related disorders (Attanasio 2008, Comeglio 2007, Katzke 2002, Liu … (more)
The c.6806T>C; p.Ile2269Thr variant (rs193922228) has been reported in multiple individuals affected with Marfan syndrome or FBN1-related disorders (Attanasio 2008, Comeglio 2007, Katzke 2002, Liu 1997, Proost 2015, Soylen 2009, Stheneur 2009), and is classified as pathogenic/likely pathogenic in ClinVar (variant ID 36107). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism). The isoleucine at codon 2269 is a highly conserved residue located within the calcium-binding EGF-like domain. Based on the above information, this variant is likely to be pathogenic. (less)
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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: SCV002025420.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
Comment:
PM2, PS1, PP4
Number of individuals with the variant: 2
Sex: male
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Pathogenic
(Mar 01, 2017)
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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: SCV000695589.3
First in ClinVar: Mar 17, 2018 Last updated: Dec 11, 2022 |
Comment:
Variant summary: The FBN1 c.6806T>C (p.Ile2269Thr) variant involves the missense alteration of a conserved nucleotide. The variant falls within a highly conserved EGF-like calcium binding … (more)
Variant summary: The FBN1 c.6806T>C (p.Ile2269Thr) variant involves the missense alteration of a conserved nucleotide. The variant falls within a highly conserved EGF-like calcium binding domain #35 and 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in the large control population ExAC (0/121388 control chromosomes). Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic or pathogenic, and numerous publications in the literature have reported the variant in affected individuals, including 2 cases where patients had the variant as a de novo mutational event. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Sep 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961507.15
First in ClinVar: Oct 08, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(May 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Acromicric dysplasia
Ectopia lentis 1, isolated, autosomal dominant Marfan syndrome Stiff skin syndrome MASS syndrome Weill-Marchesani syndrome 2, dominant Geleophysic dysplasia 2 Progeroid and marfanoid aspect-lipodystrophy syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611193.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Pathogenic
(Jan 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000058900.5
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
The p.Ile2269Thr variant in FBN1 has been reported in 9 individuals with Marfan syndrome or features of Marfan syndrome, including 2 individuals in whom the … (more)
The p.Ile2269Thr variant in FBN1 has been reported in 9 individuals with Marfan syndrome or features of Marfan syndrome, including 2 individuals in whom the var iant occurred de novo (Katzke 2002, Comeglio 2007, Attanasio 2008, Stheneur 2009 , Soylen 2009, Proost 2015, LMM unpublished data). This variant was absent from large population studies. Computational prediction tools and conservation analys is suggest that this variant may impact the protein. In summary, the p.Ile2269Th r variant meets our criteria to be classified as pathogenic for Marfan syndrome in an autosomal dominant manner based upon presence in affected individuals, abs ence from controls and de novo occurrences. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 29, 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: SCV000322364.11
First in ClinVar: Oct 09, 2016 Last updated: Oct 05, 2023 |
Comment:
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; … (more)
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; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 10464652, 16342915, 24793577, 17657824, 25907466, 12938084, 18435798, 12203992, 19159394, 27611364, 35058154, 19293843, 31098894, 29848614) (less)
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Pathogenic
(Nov 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: SCV000627974.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2269 of the FBN1 protein (p.Ile2269Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2269 of the FBN1 protein (p.Ile2269Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 10464652, 12203992, 16342915, 18435798, 19159394, 19293843, 25907466, 27611364). ClinVar contains an entry for this variant (Variation ID: 36107). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 01, 2021)
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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: SCV000320238.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
The p.I2269T pathogenic mutation (also known as c.6806T>C), located in coding exon 55 of the FBN1 gene, results from a T to C substitution at … (more)
The p.I2269T pathogenic mutation (also known as c.6806T>C), located in coding exon 55 of the FBN1 gene, results from a T to C substitution at nucleotide position 6806. The isoleucine at codon 2269 is replaced by threonine, an amino acid with similar properties, and is located in the cbEGF-like #35 domain. This variant has been detected in multiple individuals with a clinical diagnosis of Marfan syndrome (MFS) and was reported to be de novo in two of the probands (Katzke S et al, Hum. Mutat. 2002; 20(3):197-208; Attanasio M et al, Clin. Genet. 2008l; 74(1):39-46; Söylen B et al, Clin. Genet. 2009; 75(3):265-70; Stheneur C et al. Eur. J. Hum. Genet. 2009;17:1121-8; Proost D et al. Hum. Mutat. 2015;36:808-14). This variant has also been identified in several cohorts with aortic or connective tissue disease (Liu WO et al, Genet. 1997/98; 1(4):237-42; Comeglio P et al. Hum. Mutat. 2007;28:928; Yang H et al. Sci Rep. 2016;6:33002). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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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: SCV000787271.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 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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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 |
Impact of Pathogenic FBN1 Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome. | Takeda N | Circulation. Genomic and precision medicine | 2018 | PMID: 29848614 |
Genetic testing of 248 Chinese aortopathy patients using a panel assay. | Yang H | Scientific reports | 2016 | PMID: 27611364 |
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 |
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 |
Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations. | Söylen B | Clinical genetics | 2009 | PMID: 19159394 |
FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. | Attanasio M | Clinical genetics | 2008 | PMID: 18435798 |
The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. | Comeglio P | Human mutation | 2007 | PMID: 17657824 |
Marfan syndrome--a diagnostic challenge caused by phenotypic and genetic heterogeneity. | Baumgartner C | Methods of information in medicine | 2005 | PMID: 16342915 |
Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. | Collod-Béroud G | Human mutation | 2003 | PMID: 12938084 |
TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. | Katzke S | Human mutation | 2002 | PMID: 12203992 |
Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders. | Liu WO | Genetic testing | 1997 | PMID: 10464652 |
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Text-mined citations for rs193922228 ...
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.