ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.2861G>A (p.Arg954His)
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.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000138.5(FBN1):c.2861G>A (p.Arg954His)
Variation ID: 200005 Accession: VCV000200005.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48490072 (GRCh38) [ NCBI UCSC ] 15: 48782269 (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 Jul 5, 2015 May 1, 2024 Dec 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.2861G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Arg954His missense NC_000015.10:g.48490072C>T NC_000015.9:g.48782269C>T NG_008805.2:g.160717G>A LRG_778:g.160717G>A LRG_778t1:c.2861G>A LRG_778p1:p.Arg954His - Protein change
- R954H
- Other names
- p.R954H:CGC>CAC
- Canonical SPDI
- NC_000015.10:48490071:C:T
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 |
7554 | 7887 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Sep 25, 2023 | RCV000181469.9 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Oct 19, 2015 | RCV000208533.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 22, 2022 | RCV001192095.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2023 | RCV001205432.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 6, 2022 | RCV001797666.9 |
Submissions - Germline
Classification
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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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Uncertain significance
(Sep 06, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002041890.2
First in ClinVar: Dec 25, 2021 Last updated: Nov 05, 2022 |
Comment:
Variant summary: FBN1 c.2861G>A (p.Arg954His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: FBN1 c.2861G>A (p.Arg954His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251154 control chromosomes. c.2861G>A has been reported in the literature in individuals affected with Marfan Syndrome (Soylen_2009, Nayak_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: two reporting the variant as likely pathogenic and the remaining four reporting it as uncertain signficance. Another variant affecting the same codon (p.Arg954Cys), has been classifed as pathogenic by our laboratory. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Sep 25, 2023)
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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: SCV000233771.14
First in ClinVar: Jul 05, 2015 Last updated: Sep 30, 2023 |
Comment:
Identified in an adult with skeletal and ocular features of Marfan syndrome without cardiac involvement (Sylen et al., 2009); Observed as a homozygous variant in … (more)
Identified in an adult with skeletal and ocular features of Marfan syndrome without cardiac involvement (Sylen et al., 2009); Observed as a homozygous variant in a child with clinical features of Marfan syndrome; the heterozygous father was described as unaffected, while the heterozygous mother was described as having features suggestive of LeriWeill dyschondrosteosis (Nayak et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 19159394, 33436942, 12938084) (less)
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Likely pathogenic
(Oct 19, 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: SCV000263899.2
First in ClinVar: Mar 01, 2016 Last updated: Jul 21, 2018 |
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 22, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001360068.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 954 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with histidine at codon 954 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in four individuals affected with Marfan syndrome (PMID: 12938084, 19159394, 33436942). One of the probands was homozygote and the parents were heterozygous carriers with limited clinical information available. This variant has also been reported in an individual with a history of aortic dissection (communication with an external laboratory; ClinVar SCV000263899.2). This variant has been identified in 1/251154 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg954Cys, is known to be pathogenic (Clinvar variation ID 495582), indicating that arginine at this position is important for FBN1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Dec 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Familial thoracic aortic aneurysm and aortic dissection
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001376689.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 954 of the FBN1 protein (p.Arg954His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 954 of the FBN1 protein (p.Arg954His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of Marfan syndrome in the heterozygous and homozygous state (PMID: 19159394, 33436942; Invitae). ClinVar contains an entry for this variant (Variation ID: 200005). 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%. This variant disrupts the p.Arg954 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Oct 29, 2015)
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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: SCV000318124.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
The p.R954H variant (also known as c.2861G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide … (more)
The p.R954H variant (also known as c.2861G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 2861. The arginine at codon 954 is replaced by histidine, an amino acid with highly similar properties. In one study, p.R954H was detected in a 58-year-old female patient with positive wrist and thumb signs, joint hypermobility, highly arched palate with crowding of teeth, ectopia lentis, and dural ectasia. The novel alteration was reported to be familial and located in the TGF-beta like #3 module (Söylen B et al, Clin. Genet. 2009 Mar; 75(3):265-70). This variant was previously reported in the SNPDatabase as rs112911555, but was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (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: SCV000786899.1
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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Clinically relevant variants in a large cohort of Indian patients with Marfan syndrome and related disorders identified by next-generation sequencing. | Nayak SS | Scientific reports | 2021 | PMID: 33436942 |
Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations. | Söylen B | Clinical genetics | 2009 | PMID: 19159394 |
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 rs112911555 ...
HelpRecord last updated Oct 08, 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.