ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.7039_7040del (p.Met2347fs)
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.7039_7040del (p.Met2347fs)
Variation ID: 200171 Accession: VCV000200171.38
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 15q21.1 15: 48427731-48427732 (GRCh38) [ NCBI UCSC ] 15: 48719928-48719929 (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 7, 2017 May 1, 2024 Nov 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.7039_7040del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Met2347fs frameshift NM_000138.5:c.7039_7040delAT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000138.4:c.7039_7040delAT NC_000015.10:g.48427731_48427732del NC_000015.9:g.48719928_48719929del NG_008805.2:g.223057_223058del LRG_778:g.223057_223058del LRG_778t1:c.7039_7040del - Protein change
- Other names
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- Canonical SPDI
- NC_000015.10:48427730:AT:
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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
Help
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
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. |
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FBN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7456 | 7786 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 29, 2022 | RCV000181674.20 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Dec 20, 2021 | RCV000208062.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2023 | RCV000524503.13 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jan 20, 2016 | RCV000755190.8 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 7, 2022 | RCV000613882.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 2, 2021 | RCV001775090.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 25, 2019 | RCV001192804.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781410.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Pathogenic
(Feb 25, 2019)
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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: SCV001361164.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: FBN1 c.7039_7040delAT (p.Met2347ValfsX19) 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.7039_7040delAT (p.Met2347ValfsX19) 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. The variant was absent in 245612 control chromosomes (gnomAD). c.7039_7040delAT has been reported in the literature in multiple individuals affected with Marfan Syndrome (Korkko_2002, Attanasio_2008, Comeglio_2007, Yoo_2010, Baudhuin_2015). 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. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
paternal
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Laboratoire Génétique Moléculaire, CHRU TOURS
Accession: SCV001760720.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Clinical Features:
Neurodevelopmental abnormality (present)
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Pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Weill-Marchesani syndrome 2, dominant
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002012050.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Frameshift: 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 … (more)
Frameshift: 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 (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000200171.11). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Congenital diaphragmatic hernia (present) , Depressed nasal bridge (present) , Abnormal facial shape (present) , Frontal bossing (present) , Scoliosis (present) , Delayed speech and … (more)
Congenital diaphragmatic hernia (present) , Depressed nasal bridge (present) , Abnormal facial shape (present) , Frontal bossing (present) , Scoliosis (present) , Delayed speech and language development (present) (less)
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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: SCV002025431.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
Comment:
PM2, PVS1, PP4 or PM2, PVS1, PP1, PP4
Number of individuals with the variant: 5
Sex: mixed
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Pathogenic
(May 14, 2020)
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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: SCV002042012.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003924076.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
A Heterozygous Frameshift variant c.7039_7040delAT in Exon 58 of the FBN1 gene that results in the amino acid substitution p.Met2347fs*19 was identified. The observed variant … (more)
A Heterozygous Frameshift variant c.7039_7040delAT in Exon 58 of the FBN1 gene that results in the amino acid substitution p.Met2347fs*19 was identified. The observed variant novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 200171). This variant has previously been reported for Marfan syndrome (Comeglio P et al., 2007). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Nov 15, 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: SCV000283647.7
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Met2347Valfs*19) 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.Met2347Valfs*19) 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: 11826022, 17627385, 19618372, 26272055, 26621581). ClinVar contains an entry for this variant (Variation ID: 200171). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 07, 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: SCV000738824.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The c.7039_7040delAT pathogenic mutation, located in coding exon 57 of the FBN1 gene, results from a deletion of two nucleotides at nucleotide positions 7039 to … (more)
The c.7039_7040delAT pathogenic mutation, located in coding exon 57 of the FBN1 gene, results from a deletion of two nucleotides at nucleotide positions 7039 to 7040, causing a translational frameshift with a predicted alternate stop codon (p.M2347Vfs*19). This alteration has been described in multiple individuals with Marfan syndrome or related phenotypes (Körkkö J et al. J Med Genet. 2002 ;39:34-41; Howarth R et al. Genet Test. 2007;11:146-52; Comeglio P et al. Hum Mutat. 2007;28:928; Attanasio M et al. Clin Genet. 2008 ;74:39-46; Magyar I et al. Hum Mutat. 2009;30:1355-64; Yoo EH et al. Clin Genet. 2010;77:177-82; Regalado ES et al. Clin Genet. 2016 ;89:719-23; Guo J et al. Sci Rep. 2015;5:13115; Somers AE et al. Am J Med Genet A. 2016;170:1786-90). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Aug 21, 2015)
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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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Blueprint Genetics
Accession: SCV000263920.2
First in ClinVar: Mar 01, 2016 Last updated: Jul 21, 2018 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885431.1
First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017 |
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Pathogenic
(Jan 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: yes
Allele origin:
de novo
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV000928336.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
Comment:
PVS1, PM2, PP5
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Pathogenic
(Dec 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002577937.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
ACMG categories: PVS1,PP3,PP5
Number of individuals with the variant: 1
Clinical Features:
Abnormality of connective tissue (present)
Age: 30-39 years
Sex: female
Tissue: blood
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Pathogenic
(Apr 29, 2022)
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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: SCV000233977.15
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift 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; This variant is associated with the following publications: (PMID: 29357934, 11826022, 25101912, 27112580, 17627385, 19863550, 26272055, 17657824, 19618372, 18435798, 29543232, 33436942, 32679894, 34008892, 26621581) (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: SCV000731223.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Clinical Features:
Aneurysm (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: SCV000787293.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
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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: SCV000787294.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
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Likely pathogenic
(Jan 20, 2016)
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no assertion criteria provided
Method: research
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Familial thoracic aortic aneurysms
Acute aortic dissections
Affected status: yes
Allele origin:
unknown
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000883019.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
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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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The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. | Becerra-Muñoz VM | Orphanet journal of rare diseases | 2018 | PMID: 29357934 |
Analysis of TGFBR1*6A variant in individuals evaluated for Marfan syndrome. | Somers AE | American journal of medical genetics. Part A | 2016 | PMID: 27112580 |
Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections. | Regalado ES | Clinical genetics | 2016 | PMID: 26621581 |
Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events. | Baudhuin LM | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25101912 |
Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ethnic differences in clinical manifestation. | Yoo EH | Clinical genetics | 2010 | PMID: 19863550 |
Quantitative sequence analysis of FBN1 premature termination codons provides evidence for incomplete NMD in leukocytes. | Magyar I | Human mutation | 2009 | PMID: 19618372 |
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 |
FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. | Attanasio M | Clinical genetics | 2008 | PMID: 18435798 |
The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. | Comeglio P | Human mutation | 2007 | PMID: 17657824 |
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 |
Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. | Körkkö J | Journal of medical genetics | 2002 | PMID: 11826022 |
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Text-mined citations for rs794728319 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.