ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.7754T>C (p.Ile2585Thr)
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.7754T>C (p.Ile2585Thr)
Variation ID: 163462 Accession: VCV000163462.70
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q21.1 15: 48420752 (GRCh38) [ NCBI UCSC ] 15: 48712949 (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 Jan 13, 2017 Apr 20, 2024 Jan 31, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000138.5:c.7754T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Ile2585Thr missense NC_000015.10:g.48420752A>G NC_000015.9:g.48712949A>G NG_008805.2:g.230037T>C LRG_778:g.230037T>C LRG_778t1:c.7754T>C LRG_778p1:p.Ile2585Thr - Protein change
- I2585T
- Other names
- p.I2585T:ATT>ACT
- Canonical SPDI
- NC_000015.10:48420751:A:G
-
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.
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 |
7436 | 7765 |
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/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Nov 16, 2023 | RCV000150696.24 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2022 | RCV000181613.35 | |
Pathogenic (1) |
no assertion criteria provided
|
Feb 4, 2016 | RCV000415147.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 18, 2022 | RCV000515426.12 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV000524504.17 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 12, 2017 | RCV000586322.9 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 4, 2022 | RCV000766256.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 17, 2023 | RCV003448975.1 |
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
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
(Nov 10, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Marfan syndrome
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000206957.3
First in ClinVar: Feb 06, 2015 Last updated: Jul 21, 2018 |
Number of individuals with the variant: 2
|
|
Likely pathogenic
(May 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611189.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
|
|
Pathogenic
(May 12, 2017)
|
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: SCV000695606.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The FBN1 c.7754T>C (p.Ile2585Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution within a growth factor receptor cysteine-rich … (more)
Variant summary: The FBN1 c.7754T>C (p.Ile2585Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution within a growth factor receptor cysteine-rich domain and a EGF-like calcium-binding domain (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent from the large control database ExAC (0/121220 control chromosomes). In the literature, numerous Marfan syndrome and Marfan syndrome-like patients have been identified as carriers of the variant, and segregation of the allele with disease in families has been observed (Stheneur_EJHG_2009; Howarth_GT_2007), though the allele may not be fully penetrant (Poninska_J Transl Med_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic or pathogenic. Taken together, this variant is classified as pathogenic. (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: SCV000781419.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
|
|
Likely pathogenic
(Feb 07, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Marfan syndrome type 1
Affected status: yes
Allele origin:
germline
|
Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000840407.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
Number of individuals with the variant: 1
Age: 40-49 years
Sex: female
|
|
Likely pathogenic
(Nov 20, 2018)
|
criteria provided, single submitter
(ACMG Guidelines, 2015)
Method: clinical testing
|
Thoracic aortic aneurysm and aortic dissection
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf
Accession: SCV000897674.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
|
|
Pathogenic
(Feb 14, 2018)
|
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: SCV000198060.4
First in ClinVar: Feb 02, 2015 Last updated: Apr 09, 2018 |
Comment:
The p.Ile2585Thr variant in FBN1 has been reported in >15 individuals with clini cal features of Marfan syndrome (Liu 1997, Loeys 2001, Biggin 2004, Comeglio … (more)
The p.Ile2585Thr variant in FBN1 has been reported in >15 individuals with clini cal features of Marfan syndrome (Liu 1997, Loeys 2001, Biggin 2004, Comeglio 200 7, Howarth 2007, Stheneur 2009, Soylen 2009, Ogawa 2011, Aalberts 2014, Buchan 2 014, Haller 2015, Proost 2015, Yang 2016, Poninska 2016, LMM unpublished data) a nd segregated with disease in 5 affected relatives from two families (Howarth 20 07, Poninska 2016). This variant has also been reported by other clinical labora tories in ClinVar (Variation ID 163462), including a de novo occurrence in one i ndividual referred for Marfan/TAAD testing in one laboratory (SCV000233916.8). I t has been identified in 1/30782 South Asian and 1/33572 Latino chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727503054). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, this v ariant meets criteria to be classified as pathogenic for Marfan syndrome in an a utosomal dominant manner based upon presence in multiple affected individuals, s egregation studies, and de novo occurrence. ACMG/AMP Criteria applied: PS4, PM2, PP1_Moderate, PM6 (Richards 2015). (less)
Number of individuals with the variant: 3
|
|
Pathogenic
(Apr 02, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Marfan syndrome
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433471.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
|
|
Pathogenic
(Nov 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450417.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
|
|
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: SCV002025459.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
Comment:
PS4, PS1, PP4
Sex: male
|
|
Pathogenic
(Nov 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603653.4
First in ClinVar: Sep 30, 2017 Last updated: Jan 08, 2022 |
Comment:
The FBN1 c.7754T>C; p.Ile2585Thr variant (rs727503054) is reported in the literature in multiple individuals affected with Marfan syndrome (MFS) or MFS-related phenotypes (Becerra-Munoz 2018, Biggin … (more)
The FBN1 c.7754T>C; p.Ile2585Thr variant (rs727503054) is reported in the literature in multiple individuals affected with Marfan syndrome (MFS) or MFS-related phenotypes (Becerra-Munoz 2018, Biggin 2004, Collod-Beroud 2003, Comeglio 2007, Fang 2017, Haller 2015, Liu 1997-1998, Loeys 2001, Poninska 2016, Yang 2016). This variant is reported in ClinVar (Variation ID: 163462), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 2585 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious REVEL: 0.642). Based on available information, the p.Ile2585Thr variant is considered to be pathogenic. References: Becerra-Munoz VM et al. The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. Orphanet J Rare Dis. 2018 Jan 22;13(1):16. PubMed: 29357934. 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. PMID: 14695540. Collod-Beroud G et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2003 Sep;22(3):199-208. PMID: 12938084. Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. PMID: 17657824. Fang M et al. Identification of Novel Clinically Relevant Variants in 70 Southern Chinese patients with Thoracic Aortic Aneurysm and Dissection by Next-generation Sequencing. Sci Rep. 2017 Aug 30;7(1):10035. PMID: 28855619. Haller G et al. Genetic Risk for Aortic Aneurysm in Adolescent Idiopathic Scoliosis. J Bone Joint Surg Am. 2015 Sep 2;97(17):1411-7. PMID: 26333736. Liu WO et al. Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders. Genet Test. 1997-1998;1(4):237-42. PMID: 10464652. Loeys B et al. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001 Nov 12;161(20):2447-54. PMID: 11700157 Poninska JK et al. Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations. J Transl Med. 2016 May 4;14(1):115. PMID: 27146836. Yang H et al. Genetic testing of 248 Chinese aortopathy patients using a panel assay. Sci Rep. 2016 Sep 9;6:33002. PMID: 27611364. (less)
|
|
Pathogenic
(Sep 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002103256.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
PP1_moderate, PP2, PP5, PM2_supporting, PM6, PS4
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Marfan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769130.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated EGF-like domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Marfan syndrome or other Marfan syndrome related phenotypes (ClinVar, VCGS, PMID: 11700157). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
Pathogenic
(Dec 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000233916.11
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 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: 14695540, 17627385, 17657824, 27611364, 31098894, 31211626, 31751304, 32123317, 30739908, 32866347, 10464652, 21907952, 11933199, 24833718, 19293843, 24161884, 26333736, 27146836, 28855619, 27724990, 19159394, 29357934, 30675029, 25907466, 12938084, 12203992, 12203987, 31447099, 33483584, 32679894, 11700157) (less)
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001332863.2
First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023 |
|
|
Pathogenic
(Nov 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000318330.7
First in ClinVar: Oct 02, 2016 Last updated: Apr 15, 2023 |
Comment:
The p.I2585T pathogenic mutation (also known as c.7754T>C), located in coding exon 62 of the FBN1 gene, results from a T to C substitution at … (more)
The p.I2585T pathogenic mutation (also known as c.7754T>C), located in coding exon 62 of the FBN1 gene, results from a T to C substitution at nucleotide position 7754. The isoleucine at codon 2585 is replaced by threonine, an amino acid with some similar properties, and is located in the cb EGF-like #41 domain. This alteration has been reported in numerous individuals with Marfan syndrome (MFS) and MFS-related phenotypes from a variety of ethnic backgrounds (Loeys B et al. Arch Intern Med. 2001;161(20):2447-2454; Biggin A et al. Hum Mutat. 2004;23(1):99; Soylen B et al. Clin Genet. 2009;75(3):265-270; Yang H et al. Sci Rep, 2016 Sep;6:33002). In one family, six relatives across three generations were reported to have this alteration with clinical features ranging from isolated scoliosis through complete MFS (Poninska JK et al. J Transl Med, 2016 May;14:115). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
Pathogenic
(Jan 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Geleophysic dysplasia 2
Weill-Marchesani syndrome 2, dominant Ectopia lentis 1, isolated, autosomal dominant MASS syndrome Progeroid and marfanoid aspect-lipodystrophy syndrome Acromicric dysplasia Marfan syndrome Stiff skin syndrome
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV002495772.2
First in ClinVar: Apr 11, 2022 Last updated: May 06, 2023 |
Comment:
This variant has been reported in the literature in numerous individuals with a clinical diagnosis or features of Marfan syndrome, segregating with disease in at … (more)
This variant has been reported in the literature in numerous individuals with a clinical diagnosis or features of Marfan syndrome, segregating with disease in at least 2 affected family members, and has also been identified in the de novo state (Selected publications: Loeys 2001 PMID:11700157, Stheneur 2009 PMID:19293843, Haller 2015 PMID:26333736, Fang 2016 PMID:28855619, Poninska 2016 PMID:27146836, Yang 2016 PMID:27611364, Becerra Munoz 2018 PMID:29357934, Damrauer 2019 PMID:31211626, Renner 2019 PMID:30675029, Ferreira de Assis Funari 2020 PMID:31751304, Stark 2020 PMID:32679894). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID:163462). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, this variant is classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Connective tissue dysplasia
Affected status: yes
Allele origin:
germline
|
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Accession: SCV004176723.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
Heterozygous variant NM_000138:c.7754T>C (p.Ile2585Thr) in FBN1 gene was found on the WES data in female proband (65 y.o., Caucasian) with Connective tissue dysplasia and aortic … (more)
Heterozygous variant NM_000138:c.7754T>C (p.Ile2585Thr) in FBN1 gene was found on the WES data in female proband (65 y.o., Caucasian) with Connective tissue dysplasia and aortic dissection. This variant has been reported in over 30 articles with variable phenotypes. Clinvar contains entry on this variant (Variation ID: 163462). This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.00001594 (Date of access 17-01-2023). This variant has been reported in over several dozens of studies. In silico predictors are inconsistent in the results (varsome.com). In accordance with ACMG(2015) criteria and Proposal for a Disease- and Gene-Specific Guideline for the Interpretation of Sequenced Variants in the FBN1 Gene for Marfan Syndrome (PMID: 29875124), this variant is classified as Pathogenic with following criteria selected: PS4_Strong, PP5_Strong, PS5, PM2. (less)
Clinical Features:
Aortic dissection (present)
Age: 60-69 years
Sex: female
Ethnicity/Population group: Caucasian
|
|
Pathogenic
(Jan 31, 2024)
|
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: SCV000283652.11
First in ClinVar: Jul 01, 2016 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 2585 of the FBN1 protein (p.Ile2585Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2585 of the FBN1 protein (p.Ile2585Thr). This variant is present in population databases (rs727503054, gnomAD 0.003%). This missense change has been observed in individual(s) with Marfan syndrome and a FBN1-related disease (PMID: 10464652, 11700157, 14695540, 17657824, 19293843, 24833718, 26333736; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 163462). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Nov 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Marfan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004816738.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces isoleucine with threonine at codon 2585 in the EGF-like calcium-binding domain of the FBN1 protein. Computational prediction is inconclusive regarding the … (more)
This missense variant replaces isoleucine with threonine at codon 2585 in the EGF-like calcium-binding domain of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in many individuals affected with Marfan syndrome (PMID: 19293843, 24161884, 24833718, 25907466, 26333736, 27146836, 31751304, 32679894) and in individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 28855619, 30675029, 30739908, 34498425), including two individuals where the variant was observed to be de novo (PMID: 29357934, 34498425). This variant has been shown to segregate with disease in three families (PMID: 27146836, 27724990, 31751304). In one family, six carriers across three generations showed remarkable variability in clinical features, ranging from isolated scoliosis, aneurysm of the abdominal aorta, thoracic aortic aneurysm and aortic dissection through Marfan syndrome (PMID: 27146836). This variant has been identified in 4/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 3
|
|
Pathogenic
(Feb 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002497779.12
First in ClinVar: Apr 11, 2022 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Feb 04, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Aortic aneurysm
Aortic root aneurysm Joint hypermobility Scoliosis High myopia Tall stature
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492662.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
Likely pathogenic
(Nov 07, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Marfan syndrome
Affected status: yes
Allele origin:
de novo
|
Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000787357.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929922.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974299.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
Pathogenic
(Oct 09, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Marfan syndrome
Affected status: yes
Allele origin:
germline
|
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004041620.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
FBN1-Related Marfan Syndrome. | Adam MP | - | 2022 | PMID: 20301510 |
Genetic testing and clinical relevance of patients with thoracic aortic aneurysm and dissection in northwestern China. | Li J | Molecular genetics & genomic medicine | 2021 | PMID: 34498425 |
Genotype-Phenotype Correlation in Children: The Impact of FBN1 Variants on Pediatric Marfan Care. | Stark VC | Genes | 2020 | PMID: 32679894 |
Compound heterozygous mutations in FBN1 in a large family with Marfan syndrome. | McInerney-Leo AM | Molecular genetics & genomic medicine | 2020 | PMID: 31950671 |
Genetic investigation of patients with tall stature. | Vasco de Albuquerque Albuquerque E | European journal of endocrinology | 2020 | PMID: 31751304 |
FBN1 Coding Variants and Nonsyndromic Aortic Disease. | Damrauer SM | Circulation. Genomic and precision medicine | 2019 | PMID: 31211626 |
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 |
Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD). | Arnaud P | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30739908 |
Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients. | Renner S | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30675029 |
The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. | Becerra-Muñoz VM | Orphanet journal of rare diseases | 2018 | PMID: 29357934 |
Identification of Novel Clinically Relevant Variants in 70 Southern Chinese patients with Thoracic Aortic Aneurysm and Dissection by Next-generation Sequencing. | Fang M | Scientific reports | 2017 | PMID: 28855619 |
Identification of FBN1 gene mutations in Ukrainian Marfan syndrome patients. | Zhurayev R | Genetics research | 2016 | PMID: 27724990 |
Genetic testing of 248 Chinese aortopathy patients using a panel assay. | Yang H | Scientific reports | 2016 | PMID: 27611364 |
Marfan syndrome: current perspectives. | Pepe G | The application of clinical genetics | 2016 | PMID: 27274304 |
Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations. | Poninska JK | Journal of translational medicine | 2016 | PMID: 27146836 |
Genetic Risk for Aortic Aneurysm in Adolescent Idiopathic Scoliosis. | Haller G | The Journal of bone and joint surgery. American volume | 2015 | PMID: 26333736 |
Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. | Proost D | Human mutation | 2015 | PMID: 25907466 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. | Buchan JG | Human molecular genetics | 2014 | PMID: 24833718 |
Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome. | Aalberts JJ | Gene | 2014 | PMID: 24161884 |
Evaluating Japanese patients with the Marfan syndrome using high-throughput microarray-based mutational analysis of fibrillin-1 gene. | Ogawa N | The American journal of cardiology | 2011 | PMID: 21907952 |
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 |
The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. | Comeglio P | Human mutation | 2007 | PMID: 17657824 |
Application of dHPLC for mutation detection of the fibrillin-1 gene for the diagnosis of Marfan syndrome in a National Health Service Laboratory. | Howarth R | Genetic testing | 2007 | PMID: 17627385 |
Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. | Loeys B | Human mutation | 2004 | PMID: 15241795 |
Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. | Biggin A | Human mutation | 2004 | PMID: 14695540 |
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 |
Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies. | Robinson PN | Human mutation | 2002 | PMID: 12203987 |
Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: Identification of 20 novel mutations and two novel polymorphisms in the FBN1 gene. | Mátyás G | Human mutation | 2002 | PMID: 11933199 |
Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. | Loeys B | Archives of internal medicine | 2001 | PMID: 11700157 |
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 |
click to load more click to collapse |
Text-mined citations for rs727503054 ...
HelpRecord last updated Apr 20, 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.