ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.1090C>T (p.Arg364Ter)
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.1090C>T (p.Arg364Ter)
Variation ID: 199963 Accession: VCV000199963.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48520716 (GRCh38) [ NCBI UCSC ] 15: 48812913 (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 17, 2017 May 1, 2024 Nov 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.1090C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Arg364Ter nonsense NC_000015.10:g.48520716G>A NC_000015.9:g.48812913G>A NG_008805.2:g.130073C>T NG_063729.1:g.285G>A LRG_778:g.130073C>T LRG_778t1:c.1090C>T LRG_778p1:p.Arg364Ter - Protein change
- R364*
- Other names
- p.R364X:CGA>TGA
- Canonical SPDI
- NC_000015.10:48520715: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
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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 |
7455 | 7785 | |
LOC113939944 | - | - | - | GRCh38 | - | 129 |
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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 29, 2021 | RCV000181424.29 | |
Pathogenic (1) |
criteria provided, single submitter
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May 25, 2019 | RCV001000174.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2020 | RCV001175536.8 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 12, 2021 | RCV000602307.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 17, 2023 | RCV000684777.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2018 | RCV001374819.8 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 22, 2022 | RCV000457438.12 |
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
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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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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: SCV000781328.1
First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017 |
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Pathogenic
(May 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156663.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The FBN1 c.1090C>T; p.Arg364Ter variant (rs794728165) is reported in the literature in multiple individuals affected with suspected Marfan syndrome (Baudhuin 2015, Collod-Beroud 2003, Comeglio 2007, … (more)
The FBN1 c.1090C>T; p.Arg364Ter variant (rs794728165) is reported in the literature in multiple individuals affected with suspected Marfan syndrome (Baudhuin 2015, Collod-Beroud 2003, Comeglio 2007, Stheneur 2009, Tan 2017, Tjeldhorn 2006, Weerakkody 2018). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 199963), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Baudhuin L et al. Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants. J Hum Genet. 2015 60(5):241-52. Collod-Beroud G et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2003 22(3):199-208. Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 28(9):928. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 17(9):1121-8 Tan L et al. FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection. Hum Mol Genet. 2017 Dec 15;26(24):4814-4822. Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006 10(4):258-64. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422. (less)
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Pathogenic
(Mar 11, 2020)
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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: SCV001339152.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: FBN1 c.1090C>T (p.Arg364X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: FBN1 c.1090C>T (p.Arg364X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251536 control chromosomes(gnomAD). c.1090C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g. Collod-Beroud_2003, Weerakkody_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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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: SCV001439568.1
First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
Sex: mixed
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447091.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Delayed speech and language development (present) , Generalized joint hypermobility (present) , Tall stature (present) , Scoliosis (present) , Hypotonia (present) , Mild global developmental … (more)
Delayed speech and language development (present) , Generalized joint hypermobility (present) , Tall stature (present) , Scoliosis (present) , Hypotonia (present) , Mild global developmental delay (present) (less)
Sex: female
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Pathogenic
(Sep 23, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714516.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PVS1, PS4_moderate, PM2, PP1
Number of individuals with the variant: 1
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Pathogenic
(Jun 29, 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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GeneDx
Accession: SCV000233726.10
First in ClinVar: Jul 05, 2015 Last updated: Dec 19, 2017 |
Comment:
Reported numerous times in association with Marfan syndrome and/or TAAD (Collod-Beroud et al., 2003; Tjeldhorn et al., 2006; Comeglio et al., 2007; Rand-Hendriksen et al., … (more)
Reported numerous times in association with Marfan syndrome and/or TAAD (Collod-Beroud et al., 2003; Tjeldhorn et al., 2006; Comeglio et al., 2007; Rand-Hendriksen et al., 2007; Stheneur et al., 2009; Baudhuin et al., 2015; Li et al., 2018; Weerakkody et al., 2018); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic (ClinVar Variant ID# 199963; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 25652356, 27535533, 31211624, 30341550, 28973303, 19293843, 17663468, 12938084, 17657824, 17253931, 25525159, 29543232, 31825148) (less)
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Pathogenic
(May 22, 2022)
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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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3billion
Accession: SCV002521490.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant is shared with similarly affected mother (3billion dataset). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000199963 / PMID: 12938084). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Disproportionate tall stature (present)
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Pathogenic
(Jul 12, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003837687.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Nov 17, 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: SCV000544947.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg364*) in the FBN1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg364*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 12938084, 17657824, 17663468, 25652356). ClinVar contains an entry for this variant (Variation ID: 199963). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 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: SCV001747126.14
First in ClinVar: Jul 10, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 16, 2019)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847716.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg364X variant in FBN1 has been reported in at least 7 individuals with features of Marfan syndrome and segregated with disease in 2 affected … (more)
The p.Arg364X variant in FBN1 has been reported in at least 7 individuals with features of Marfan syndrome and segregated with disease in 2 affected individuals from 1 family (Collod-Béroud 2003, Comeglio 2007, Rand-Hendriksen 2007, Stheneur 2009, Baudhuin 2015, Tan 2017, Weerakkody 2018). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 199963). This nonsense variant leads to a premature termination codon at position 364, which is predicted to lead to a truncated or absent protein. Loss of function of the FBN1 gene is an established disease mechanism in autosomal dominant Marfan syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PVS1, PS4, PM2. (less)
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Pathogenic
(May 06, 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: SCV000738796.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R364* pathogenic mutation (also known as c.1090C>T), located in coding exon 9 of the FBN1 gene, results from a C to T substitution at … (more)
The p.R364* pathogenic mutation (also known as c.1090C>T), located in coding exon 9 of the FBN1 gene, results from a C to T substitution at nucleotide position 1090. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been previously described in multiple patients reported to have classic Marfan syndrome (Rand-Hendriksen S et al. Am J Med Genet. 2007;143A(17):1968-77; Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: yes
Allele origin:
unknown
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Centre for Genomic and Experimental Medicine, University of Edinburgh
Accession: SCV000731210.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Clinical Features:
Aneurysm (present) , Marfan syndrome (present) , TAAD Family History (present)
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Pathogenic
(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: SCV000786732.1
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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A targeted sequencing approach to find novel pathogenic genes associated with sporadic aortic dissection. | Li Z | Science China. Life sciences | 2018 | PMID: 30341550 |
Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. | Weerakkody R | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29543232 |
FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection. | Tan L | Human molecular genetics | 2017 | PMID: 28973303 |
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 |
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 |
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 |
Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome. | Rand-Hendriksen S | American journal of medical genetics. Part A | 2007 | PMID: 17663468 |
The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. | Comeglio P | Human mutation | 2007 | PMID: 17657824 |
Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. | Tjeldhorn L | Genetic testing | 2006 | PMID: 17253931 |
Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. | Collod-Béroud G | Human mutation | 2003 | PMID: 12938084 |
Text-mined citations for rs794728165 ...
HelpRecord last updated May 01, 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.