ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.2920C>T (p.Arg974Cys)
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.2920C>T (p.Arg974Cys)
Variation ID: 39667 Accession: VCV000039667.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48490013 (GRCh38) [ NCBI UCSC ] 15: 48782210 (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 Jun 10, 2015 May 1, 2024 Nov 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.2920C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Arg974Cys missense NC_000015.10:g.48490013G>A NC_000015.9:g.48782210G>A NG_008805.2:g.160776C>T LRG_778:g.160776C>T LRG_778t1:c.2920C>T LRG_778p1:p.Arg974Cys - Protein change
- R974C
- Other names
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- Canonical SPDI
- NC_000015.10:48490012: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 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 |
7436 | 7765 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 27, 2017 | RCV000032871.36 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2012 | RCV000172857.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 25, 2020 | RCV000726909.18 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 16, 2023 | RCV001186221.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 6, 2023 | RCV001192805.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2023 | RCV000548224.14 |
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
(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: SCV000781346.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
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Pathogenic
(Dec 28, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000704117.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Feb 25, 2020)
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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: SCV001474003.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The FBN1 c.2920C>T; p.Arg974Cys variant (rs397514558) is reported in the literature in several individuals affected with Marfan syndrome (Comeglio 2007, Stheneur 2009). This variant is … (more)
The FBN1 c.2920C>T; p.Arg974Cys variant (rs397514558) is reported in the literature in several individuals affected with Marfan syndrome (Comeglio 2007, Stheneur 2009). This variant is also reported to segregate in all affected members of a large, multigenerational kindred affected with ectopia lentis (Yang 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 974 is moderately conserved, it occurs in one of the TGF-beta binding (TB) domains (Yuan 1997), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. TB domains contain eight conserved cysteine residues and the disulfide bridges formed between these residues are essential for protein folding; loss of one of these cysteines or creation of a new cysteine in this domain may interfere with proper disulfide bridge formation, disrupting protein structure (Yuan 1997). Accordingly, the revised Ghent nosology for Marfan syndrome lists missense variants creating or affecting cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 47(7): 476-85. 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 Sep;17(9):1121-8. Yang G et al. A novel FBN1 mutation in a Chinese family with isolated ectopia lentis. Mol Vis. 2012;18:945-50. Yuan X et al. Solution structure of the transforming growth factor beta-binding protein-like module, a domain associated with matrix fibrils. EMBO J. 1997 Nov 17;16(22):6659-66. (less)
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Pathogenic
(Nov 16, 2023)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001352587.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 974 in the TGFbeta-like motif 5 of the FBN1 protein. Cysteine creating variants in TGF-beta binding … (more)
This missense variant replaces arginine with cysteine at codon 974 in the TGFbeta-like motif 5 of the FBN1 protein. Cysteine creating variants in TGF-beta binding domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Marfan syndrome or isolated ectopia lentis (PMID: 17627385, 17657824, 22539873, 25053872, 28941062, 34140103, 34281902, ClinVar SCV000845663.2). This variant has been shown to segregate with isolated ectopia lentis in one of the families (PMID: 22539873). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Apr 19, 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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Ambry Genetics
Accession: SCV000738929.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R974C pathogenic mutation (also known as c.2920C>T), located in coding exon 24 of the FBN1 gene, results from a C to T substitution at … (more)
The p.R974C pathogenic mutation (also known as c.2920C>T), located in coding exon 24 of the FBN1 gene, results from a C to T substitution at nucleotide position 2920. The arginine at codon 974 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the TGFBP#03 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues (Collod-Béroud G et al. Hum. Mut. 2003:22(3):199-208). This particular mutation has been reported in a number of Marfan syndrome (MFS) and ectopia lentis (EL) cohorts (Comeglio P et al. Hum. Mutat. 2007;28:928; Howarth R et al. Genet. Test. 2007;11:146-52; Stheneur C et al. Eur. J. Hum. Genet. 2009;17:1121-8; Li J et al. Mol. Vis. 2014;20:1017-24; Vatti L et al. Am. J. Med. Genet. A. 2017;173:2995-3002). This variant also segregated with ectopia lentis in one large Chinese family (Yang G et al. Mol. Vis. 2012;18:945-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Likely pathogenic
(Jul 27, 2017)
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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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Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub
Accession: SCV000845663.2
First in ClinVar: Jul 21, 2018 Last updated: Dec 11, 2022 |
Comment:
The FBN1 c.2920C>T variant has previously been reported in 9 affected members of a 5 generation family with isolated ectopia lentis (Yang et al. Mol … (more)
The FBN1 c.2920C>T variant has previously been reported in 9 affected members of a 5 generation family with isolated ectopia lentis (Yang et al. Mol Vis. 2012;18:945-50) and a single patient with Marfan syndrome with major skeletal, ocular and cardiovascular manifestations (Comeglio et al. Hum Mutat. 2007 ;28(9):928). It has not been detected in approximately 120,000 individuals in control populations (gnomAD database). In silico tools predict the variant will adversely affect protein structure and function and it affects a highly conserved TGFB binding domain. This variant is therefore likely to be pathogenic, but may be associated with a variable phenotype. - Other Disease Reports - This variant has been linked to other diseases: Ectopia lentis (pubmed: 22539873) - Missense Effect Predictions - 87.5% (7/8) of algorithms have predicted that this variant will adversely affect protein function (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 06, 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: SCV001361165.2
First in ClinVar: Jun 22, 2020 Last updated: Mar 26, 2023 |
Comment:
Variant summary: FBN1 c.2920C>T (p.Arg974Cys) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Five of … (more)
Variant summary: FBN1 c.2920C>T (p.Arg974Cys) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes. c.2920C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g. Comeglio_2007, Howarth_2007, Li_2014, Vatti_2017, Lopez-Sainz_2021). The variant has also been reported to cosegregate with disease in families with an Ectopia Lentis phenotype without other reported symptoms of Marfan Syndrome (Yang_2012, Chen_2022). 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 (other) submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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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: SCV000627874.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 974 of the FBN1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 974 of the FBN1 protein (p.Arg974Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with isolated ectopia lentis and Marfan syndrome (PMID: 17627385, 17657824, 22539873). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39667). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2012)
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no assertion criteria provided
Method: literature only
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ECTOPIA LENTIS 1, ISOLATED, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000223833.1
First in ClinVar: Jun 10, 2015 Last updated: Jun 10, 2015 |
Comment on evidence:
In a 55-year-old patient with Marfan syndrome (MFS; 154700), who had major skeletal, ocular, and cardiovascular manifestations as well as minor skin involvement, Comeglio et … (more)
In a 55-year-old patient with Marfan syndrome (MFS; 154700), who had major skeletal, ocular, and cardiovascular manifestations as well as minor skin involvement, Comeglio et al. (2007) identified heterozygosity for a c.2920C-T transition in the FBN1 gene, resulting in an arg974-to-cys (R974C) substitution. In 9 affected members of a 5-generation Chinese family with isolated ectopia lentis (ECTOL1; 129600), Yang et al. (2012) identified heterozygosity for the 2920C-T transition in exon 25 of the FBN1 gene, resulting in an R974C substitution at a highly conserved residue in the 8-cys repeat latent transforming growth factor-beta binding protein (LTBP) motif. The mutation was not found in 2 unaffected family members or in 50 ethnically matched controls. (less)
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Pathogenic
(Jan 01, 2012)
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no assertion criteria provided
Method: literature only
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MARFAN SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056641.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 10, 2015 |
Comment on evidence:
In a 55-year-old patient with Marfan syndrome (MFS; 154700), who had major skeletal, ocular, and cardiovascular manifestations as well as minor skin involvement, Comeglio et … (more)
In a 55-year-old patient with Marfan syndrome (MFS; 154700), who had major skeletal, ocular, and cardiovascular manifestations as well as minor skin involvement, Comeglio et al. (2007) identified heterozygosity for a c.2920C-T transition in the FBN1 gene, resulting in an arg974-to-cys (R974C) substitution. In 9 affected members of a 5-generation Chinese family with isolated ectopia lentis (ECTOL1; 129600), Yang et al. (2012) identified heterozygosity for the 2920C-T transition in exon 25 of the FBN1 gene, resulting in an R974C substitution at a highly conserved residue in the 8-cys repeat latent transforming growth factor-beta binding protein (LTBP) motif. The mutation was not found in 2 unaffected family members or in 50 ethnically matched controls. (less)
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Likely 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: SCV000786902.1
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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Fibrillin-1 gene mutations in a Chinese cohort with congenital ectopia lentis: spectrum and genotype-phenotype analysis. | Chen Z | The British journal of ophthalmology | 2022 | PMID: 34281902 |
Aortic Branch Aneurysms and Vascular Risk in Patients With Marfan Syndrome. | Lopez-Sainz A | Journal of the American College of Cardiology | 2021 | PMID: 34140103 |
Variability in gene-based knowledge impacts variant classification: an analysis of FBN1 missense variants in ClinVar. | Baudhuin LM | European journal of human genetics : EJHG | 2019 | PMID: 31227806 |
A cohort study of multiple families with FBN1 p.R650C variant, ectopia lentis, and low but not absent risk for aortopathy. | Vatti L | American journal of medical genetics. Part A | 2017 | PMID: 28941062 |
Mutation survey of candidate genes in 40 Chinese patients with congenital ectopia lentis. | Li J | Molecular vision | 2014 | PMID: 25053872 |
A novel FBN1 mutation in a Chinese family with isolated ectopia lentis. | Yang G | Molecular vision | 2012 | PMID: 22539873 |
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 |
Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. | Faivre L | American journal of human genetics | 2007 | PMID: 17701892 |
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 |
The molecular genetics of Marfan syndrome and related disorders. | Robinson PN | Journal of medical genetics | 2006 | PMID: 16571647 |
Consequences of cysteine mutations in calcium-binding epidermal growth factor modules of fibrillin-1. | Vollbrandt T | The Journal of biological chemistry | 2004 | PMID: 15161917 |
Positive (99mTc) diphosphonate and 67 Ga-citrate scans in ameloblastoma: case report. | Olson WH | Journal of nuclear medicine : official publication, Society of Nuclear Medicine | 1977 | PMID: 845663 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FBN1 | - | - | - | - |
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Text-mined citations for rs397514558 ...
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.