ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.7726C>T (p.Arg2576Cys)
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.7726C>T (p.Arg2576Cys)
Variation ID: 36118 Accession: VCV000036118.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48420780 (GRCh38) [ NCBI UCSC ] 15: 48712977 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 8, 2024 May 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.7726C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Arg2576Cys missense NC_000015.10:g.48420780G>A NC_000015.9:g.48712977G>A NG_008805.2:g.230009C>T LRG_778:g.230009C>T LRG_778t1:c.7726C>T LRG_778p1:p.Arg2576Cys - Protein change
- R2576C
- Other names
- FBN1, ARG2576CYS (rs147195031)
- Canonical SPDI
- NC_000015.10:48420779:G:A
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 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 |
7560 | 7893 |
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
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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no classifications from unflagged records (1) |
no classifications from unflagged records
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May 30, 2024 | RCV000029780.5 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 1, 2013 | RCV000083258.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 22, 2023 | RCV000539171.9 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 14, 2024 | RCV000788741.10 | |
Isolated thoracic aortic aneurysm
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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2018 | RCV001374808.1 |
Pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2022 | RCV002399340.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 5, 2023 | RCV003492302.2 | |
FBN1-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Jan 20, 2024 | RCV004532416.2 |
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
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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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Pathogenic
(Dec 05, 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: SCV000052434.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 04, 2024 |
Comment:
Variant summary: FBN1 c.7726C>T (p.Arg2576Cys) results in a non-conservative amino acid change, introducing a novel cysteine in the EGF-like domain (IPR000742), which is functionally important … (more)
Variant summary: FBN1 c.7726C>T (p.Arg2576Cys) results in a non-conservative amino acid change, introducing a novel cysteine in the EGF-like domain (IPR000742), which is functionally important to form disulfide bonds in FBN1. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-06 in 1461742 control chromosomes (gnomAD). This variant was found to co-segregate with Marfan Syndrome in 3 patients in our internal testing family with detailed clinical information. Additionally, c.7726C>T has been reported in the literature in at least three individuals affected with Marfan Syndrome who met Ghent criteria (e.g. Aalberts_2014, Xu_2020, Mariucci_2021), one suspected MFS patient who didn't meet Ghent criteria (Baudhuin_2015), and in at least one individual with sporadic thoracic aortic aneurysm and dissections (e.g. Guo_2015). These data indicate that the variant is very likely to be associated with disease. The variant has also been reported in the homozygous state in a patient who had clinical features that were not considered typical for Marfan Syndrome and a lack of MFS symptoms in her parents (mother confirmed to carry this variant in heterozygous state; Hogue_2012) which suggests the pathogenicity of this variant in dominant form may be modified in certain conditions. 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: 24161884, 25652356, 26787436, 26272055, 23278365, 33824467, 33711475, 31830381). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classified the variant as pathogenic/likely pathogenic and two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002670581.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R2576C pathogenic mutation (also known as c.7726C>T), located in coding exon 62 of the FBN1 gene, results from a C to T substitution at … (more)
The p.R2576C pathogenic mutation (also known as c.7726C>T), located in coding exon 62 of the FBN1 gene, results from a C to T substitution at nucleotide position 7726. The arginine at codon 2576 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #41 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This variant has been detected in several individuals with Marfan syndrome (MFS), in MFS cohorts, and in individuals with aortic aneurysm/dissection or other features of MFS (Aalberts JJ et al. Gene. 2014;534(1):40-3; Baudhuin LM et al. J Hum Genet. 2015 May;60(5):241-52; Guo J. Sci Rep. 2015 Aug;5:13115; Franken R et al. Eur Heart J. 2016 Nov;37(43):3285-3290; Li Y et al. Eur J Hum Genet. 2021 07;29(7):1129-1138; Ambry internal data). This variant was observed in a homozygous patient with severe features of MFS and other clinical findings; however, the patient's heterozygous mother reportedly did not have MFS phenotype (Hogue J et al. Clin Genet. 2013;84(4):392-3). Based on internal structural analysis, this variant may interfere with disulfide formation by forming alternative disulfide bonds, thereby perturbing the structure of a flexible loop; however, the role of this loop and its structure on the function of FBN1 is unclear (Bersch B et al. Biochemistry, 1998 Feb;37:1204-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 28, 2018)
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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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Blueprint Genetics
Accession: SCV000927966.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Aorta Panel
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Likely pathogenic
(Sep 01, 2018)
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criteria provided, single submitter
Method: research
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Isolated thoracic aortic aneurysm
Affected status: yes
Allele origin:
germline
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Department of Vascular Biology, Beijing Anzhen Hospital
Accession: SCV001439509.1
First in ClinVar: Apr 28, 2021 Last updated: Apr 28, 2021 |
Sex: mixed
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Likely pathogenic
(Apr 25, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003832856.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 22, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000627996.8
First in ClinVar: Dec 26, 2017 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: 36118). This missense change has been observed in individuals with Marfan syndrome (PMID: 23278365, 24161884, 26272055, 26787436; Invitae). This variant is present in population databases (rs147195031, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2576 of the FBN1 protein (p.Arg2576Cys). (less)
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Likely pathogenic
(May 14, 2024)
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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: SCV001805784.5
First in ClinVar: Aug 21, 2021 Last updated: Sep 16, 2024 |
Comment:
Introduces a new cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the … (more)
Introduces a new cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16571647, 17701892, 12938084, 24698609, 26787436, 16677079, 15161917, 4750422, 26272055, 33824467, 23278365, 24161884) (less)
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Pathogenic
(Oct 01, 2013)
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no assertion criteria provided
Method: literature only
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MARFAN SYNDROME, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000115337.4
First in ClinVar: Feb 11, 2014 Last updated: Jun 09, 2024 |
Comment on evidence:
In a Mexican American woman with Marfan syndrome (MFS; 154700), born of a consanguineous union, Hogue et al. (2013) identified homozygosity for a C-to-T transition … (more)
In a Mexican American woman with Marfan syndrome (MFS; 154700), born of a consanguineous union, Hogue et al. (2013) identified homozygosity for a C-to-T transition at nucleotide 7726 of the FBN1 gene, resulting in an arg-to-cys substitution at codon 2576 (R2576C). The severe phenotype included pectus carinatum, scoliosis, arachnodactyly, ectopia lentis, mitral valve prolapse, aortic dilation, dural ectasias, and anterior sacral meningocele. She had a narrow, asymmetric face, dolichocephaly, hypertelorism with an interpupillary distance of 6.4 cm, downslanting palpebral fissures, and kyphoscoliosis. She also had moderate hydrocephalus and mild cognitive impairment. At 18 years, her height was 155 cm (10th percentile), with a span-to-height ratio of 1.05. At 20 years of age she became pregnant. Her aortic root was 4.3 cm at 14 weeks' gestation. At 30 weeks she developed chest pain and dyspnea; CT scan showed new aortic insufficiency and dilation. Cesarean section and aortic root repair of a type A dissection were performed. Her son was small for gestational age but healthy. He had dolichocephaly, downslanting palpebral fissures, midface hypoplasia, high narrow palate, and mild right knee contracture. Ophthalmology exam and echocardiogram were normal. The proband's mother had no stigmata of Marfan syndrome; the proband's father had had a cardiac event attributed to drug abuse. He reportedly had no other features of Marfan syndrome, but was unavailable for examination. The R2576C mutation was not present in the Exome Variant Server or the database of FBN1 mutations, but was recorded as rs147195031 with an estimated heterozygosity score of 0 +/- 0.015. Hogue et al. (2013) concluded that presumably this is a hypomorphic allele of FBN1, not causing disease when present in heterozygosity but leading to severe disease in homozygosity. (less)
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Pathogenic
(Jan 20, 2024)
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no assertion criteria provided
Method: clinical testing
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FBN1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004730048.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The FBN1 c.7726C>T variant is predicted to result in the amino acid substitution p.Arg2576Cys. This variant was reported in multiple individuals with Marfan syndrome and/or … (more)
The FBN1 c.7726C>T variant is predicted to result in the amino acid substitution p.Arg2576Cys. This variant was reported in multiple individuals with Marfan syndrome and/or related aortopathies (Table S1, Aalberts et al. 2014. PubMed ID: 24161884; Guo et al. 2015. PubMed ID: 26272055; Table S2, Franken et al. 2016. PubMed ID: 26787436; Table S3, Li. 2021 et al. PubMed ID: 33824467). This variant was also documented in the apparently homozygous state in an individual with severe Marfan syndrome. The mother was reported to be a heterozygous carrier without clinical features of Marfan syndrome and the father was not available for examination (Hogue et al. 2013. PubMed ID: 23278365). At PreventionGenetics, this variant was identified to have occurred de novo in an individual with Marfan syndrome (internal data). This variant creates a cysteine residue that is located within the epidermal growth factor-like domain of the FBN1 protein and missense variants in FBN1 that substitute or create a cysteine residue are well-documented to cause Marfan syndrome (Dietz and Dietz. 1993. PubMed ID: 20301510; Comeglio et al. 2007. PubMed ID: 17657824; Stheneur et al. 2009. PubMed ID: 19293843). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Uncertain significance
(Nov 07, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older and 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: SCV000787353.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
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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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Evaluating the monogenic contribution and genotype-phenotype correlation in patients with isolated thoracic aortic aneurysm. | Li Y | European journal of human genetics : EJHG | 2021 | PMID: 33824467 |
Coronary Artery Aneurysms in Patients With Marfan Syndrome: Frequent, Progressive, and Relevant. | Mariucci E | The Canadian journal of cardiology | 2021 | PMID: 33711475 |
Risk Factors and Inadequacy of Screening for Sleep-Disordered Breathing in Children with Marfan Syndrome. | MacKintosh EW | Pediatric cardiology | 2021 | PMID: 33394117 |
Increased frequency of FBN1 frameshift and nonsense mutations in Marfan syndrome patients with aortic dissection. | Xu S | Molecular genetics & genomic medicine | 2020 | PMID: 31830381 |
Genotype impacts survival in Marfan syndrome. | Franken R | European heart journal | 2016 | PMID: 26787436 |
Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD. | Guo J | Scientific reports | 2015 | PMID: 26272055 |
Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants. | Baudhuin LM | Journal of human genetics | 2015 | PMID: 25652356 |
Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome. | Aalberts JJ | Gene | 2014 | PMID: 24161884 |
Homozygosity for a FBN1 missense mutation causes a severe Marfan syndrome phenotype. | Hogue J | Clinical genetics | 2013 | PMID: 23278365 |
Solution structure of the epidermal growth factor (EGF)-like module of human complement protease C1r, an atypical member of the EGF family. | Bersch B | Biochemistry | 1998 | PMID: 9477945 |
Text-mined citations for rs147195031 ...
HelpRecord last updated Oct 13, 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.