ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.7167_7168del (p.Cys2390fs)
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.7167_7168del (p.Cys2390fs)
Variation ID: 42420 Accession: VCV000042420.22
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 15q21.1 15: 48427603-48427604 (GRCh38) [ NCBI UCSC ] 15: 48719800-48719801 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 31, 2015 Feb 28, 2024 Jun 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.7167_7168del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Cys2390fs frameshift NM_000138.4:c.7167_7168delCT NC_000015.10:g.48427603AG[1] NC_000015.9:g.48719800AG[1] NG_008805.2:g.223183CT[1] LRG_778:g.223183CT[1] LRG_778t1:c.7167_7168del - Protein change
- C2390fs
- Other names
- NM_000138.4(FBN1):c.7165_7166CT[1]
- Canonical SPDI
- NC_000015.10:48427602:AGAG:AG
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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 |
7436 | 7765 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
reviewed by expert panel
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Jun 15, 2023 | RCV000035265.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 12, 2014 | RCV000181675.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 29, 2016 | RCV000589510.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2023 | RCV003764666.1 |
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
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jun 15, 2023)
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reviewed by expert panel
Method: curation
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Marfan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen FBN1 Variant Curation Expert Panel, ClinGen
Accession: SCV003933666.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
The NM_00138 c.7165_7166, is a frameshift variant in FBN1 is predicted to result in a premature stop codon at position 2404. It is expected to … (more)
The NM_00138 c.7165_7166, is a frameshift variant in FBN1 is predicted to result in a premature stop codon at position 2404. It is expected to cause a shift in the reading frame and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with a diagnosis of Marfan syndrome, with thoracic aortic aneurysm, skeletal features, which is a highly specific phenotype for Marfan syndrome (internal data) (PP4). This variant, also described as c.7167_7169del2 or p.Leu2389fsX16 using alternate nomenclature, has also been described in three other probands with a clinical diagnosis of Marfan syndrome (PMID 25907466, 17657824, internal data) and in three probands suspected of having Marfan syndrome (PMID 24793577, 14695540, internal data) (PS4). The variant has been identified as a de novo occurrence in an individual with a phenotype consistent with the gene but not highly specific (PM6_Supportive). This variant has been reported 5 times in ClinVar as pathogenic (Variantion ID: 42420). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PS4, PM6_Supportive, PM2_Supportive, PP4 (less)
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Pathogenic
(Apr 29, 2016)
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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: SCV000695596.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.7167_7168delCT variant results in a premature termination codon, predicted to cause a truncated or absent FBN1 protein, which is a commonly known … (more)
Variant summary: The c.7167_7168delCT variant results in a premature termination codon, predicted to cause a truncated or absent FBN1 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.7180C>T, p.Arg2394X; c.8326C>T, p.Arg2776X). The variant is absent from the large, broad ExAC control population. The variant has been reported in multiple affected MFS patients from the literature and has been reported by multiple reputable clinical labs as "Pathogenic". Taken together, this variant has been classified as a Pathogenic. (less)
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Pathogenic
(Mar 12, 2014)
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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: SCV000233978.10
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
The c.7167_7168delCT mutation in the FBN1 gene has been reported in one individual with Marfan or Marfan-like syndrome (reported as c.7167_7169del2 or p.Leu2389fsX16, using alternate … (more)
The c.7167_7168delCT mutation in the FBN1 gene has been reported in one individual with Marfan or Marfan-like syndrome (reported as c.7167_7169del2 or p.Leu2389fsX16, using alternate nomenclature; Biggin et al., 2004). This individual had a positive wrist and thumb sign, joint hypermobility, highly arched palate with dental crowding, characteristic facial appearance, dilated aorta, and mitral valve prolapse. The c.7167_7168delCT mutation involves the latent transforming growth factor b1 binding protein (LTBP) domain of the FBN1 gene (Biggin et al., 2004). Additionally, c.7167_7168delCT wasnot observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation causes a shift in reading frame starting at codon Cysteine 2390, changing it to a Serine, and creating a premature stop codon at position 15 of the new reading frame, denoted p.Cys2390SerfsX15. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the FBN1 gene have been reported in association with Marfan syndrome. In summary, c.7167_7168delCT in the FBN1 gene is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 01, 2010)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000058912.5
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Number of individuals with the variant: 1
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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: SCV002025436.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
Comment:
PM2, PVS1, PP4
Sex: male
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Pathogenic
(May 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: SCV004570896.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42420). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42420). This variant is also known as c.7167_7169del2 (p.Leu2389fsX16). This premature translational stop signal has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 14695540). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys2390Serfs*15) 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). (less)
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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:
de novo
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Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000787305.1
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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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 |
The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. | Comeglio P | Human mutation | 2007 | PMID: 17657824 |
Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. | Biggin A | Human mutation | 2004 | PMID: 14695540 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/93fd1b32-0700-482d-8fb2-cda364449c28 | - | - | - | - |
Text-mined citations for rs397515846 ...
HelpRecord last updated Mar 05, 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.