ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.3224G>A (p.Arg1075His)
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.3224G>A (p.Arg1075His)
Variation ID: 887213 Accession: VCV000887213.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48488226 (GRCh38) [ NCBI UCSC ] 15: 48780423 (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 May 31, 2020 Apr 20, 2024 Sep 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.3224G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Arg1075His missense NC_000015.10:g.48488226C>T NC_000015.9:g.48780423C>T NG_008805.2:g.162563G>A LRG_778:g.162563G>A LRG_778t1:c.3224G>A - Protein change
- R1075H
- Other names
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- Canonical SPDI
- NC_000015.10:48488225: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.
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Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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
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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
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 |
7570 | 7903 |
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
Help
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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Apr 28, 2017 | RCV001119807.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001119806.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001119808.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 4, 2023 | RCV001119809.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 9, 2023 | RCV001119810.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001119811.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 16, 2023 | RCV001361472.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 13, 2023 | RCV002282459.4 |
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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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ectopia lentis 1, isolated, autosomal dominant
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001278250.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Weill-Marchesani syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001278255.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Acromicric dysplasia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001278251.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Stiff skin syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001278252.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001278253.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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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
|
Illumina Laboratory Services, Illumina
Accession: SCV001278254.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jul 13, 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: SCV002571386.4
First in ClinVar: Sep 17, 2022 Last updated: Jul 29, 2023 |
Comment:
Identified as a maternally-inherited variant in a 30 year old Japanese male; both individuals were reported to be healthy and have no features of Marfan … (more)
Identified as a maternally-inherited variant in a 30 year old Japanese male; both individuals were reported to be healthy and have no features of Marfan syndrome (Ikebuchi et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; 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: 12203992, 10679954, 12938084) (less)
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Uncertain significance
(Feb 09, 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: SCV001341879.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 1075 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with histidine at codon 1075 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two healthy, related individuals who showed no signs of Marfan syndrome or aortic aneurysms (PMID: 10679954). This variant has been identified in 6/282848 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 16, 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: SCV001557448.4
First in ClinVar: Apr 13, 2021 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 1075 of the FBN1 protein (p.Arg1075His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1075 of the FBN1 protein (p.Arg1075His). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 887213). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is present in population databases (rs369745372, gnomAD 0.01%). (less)
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Uncertain Significance
(Sep 04, 2023)
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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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All of Us Research Program, National Institutes of Health
Accession: SCV004814823.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces arginine with histidine at codon 1075 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with histidine at codon 1075 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 two healthy, related individuals who showed no signs of Marfan syndrome or aortic aneurysms (PMID: 10679954). This variant has been identified in 6/282848 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 5
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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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TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. | Katzke S | Human mutation | 2002 | PMID: 12203992 |
The Arg1075His substitution in the FBN1 gene is clinically innocent for Marfan syndrome. | Ikebuchi M | Human mutation | 2000 | PMID: 10679954 |
Text-mined citations for rs369745372 ...
HelpRecord last updated Sep 29, 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.