ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.185G>A (p.Arg62His)
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.
Uncertain significance(9); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000138.5(FBN1):c.185G>A (p.Arg62His)
Variation ID: 42296 Accession: VCV000042296.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48613072 (GRCh38) [ NCBI UCSC ] 15: 48905269 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 31, 2015 Apr 20, 2024 Dec 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.185G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Arg62His missense NC_000015.10:g.48613072C>T NC_000015.9:g.48905269C>T NG_008805.2:g.37717G>A LRG_778:g.37717G>A LRG_778t1:c.185G>A LRG_778p1:p.Arg62His - Protein change
- R62H
- Other names
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- Canonical SPDI
- NC_000015.10:48613071: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 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00012
Exome Aggregation Consortium (ExAC) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00012
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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FBN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7436 | 7765 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000035130.12 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 20, 2016 | RCV000755193.8 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 3, 2022 | RCV000757273.19 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2023 | RCV000777703.13 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 2, 2023 | RCV001046446.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 14, 2023 | RCV000781355.12 |
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
(Aug 28, 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: SCV000885429.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
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Uncertain significance
(Oct 15, 2020)
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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: SCV001815271.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Has been previously observed in individuals referred for Marfan or Marfan-like syndromes (Lerner-Ellis et al., 2014; Regalado et al., 2015; Becerra-Muoz et al., 2018).; In … (more)
Has been previously observed in individuals referred for Marfan or Marfan-like syndromes (Lerner-Ellis et al., 2014; Regalado et al., 2015; Becerra-Muoz et al., 2018).; 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 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: 29357934, 26621581, 22102435, 24793577) (less)
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Uncertain significance
(May 04, 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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Mendelics
Accession: SCV002517074.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Uncertain significance
(Aug 09, 2016)
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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: SCV000738792.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R62H variant (also known as c.185G>A), located in coding exon 2 of the FBN1 gene, results from a G to A substitution at nucleotide … (more)
The p.R62H variant (also known as c.185G>A), located in coding exon 2 of the FBN1 gene, results from a G to A substitution at nucleotide position 185. The arginine at codon 62 is replaced by histidine, an amino acid with highly similar properties, and is located in the 4-cys motif LTBP-like domain. This alteration was reported in a patient with Marfan syndrome (Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6), as well as in one with thoracic aortic aneurysms and dissection (Regalado ES et al. Clin. Genet., 2016 Jun;89:719-23). This variant was previously reported in the SNPDatabase as rs145942328. Based on data from ExAC, the A allele has an overall frequency less than 0.01% (6/105960). Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12986) total alleles studied, having been observed in 0.02% (1/4394) African American alleles. This amino acid position is well conserved in available vertebrate species; however, histidine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Dec 30, 2017)
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criteria provided, single submitter
Method: curation
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Marfan syndrome
Affected status: yes
Allele origin:
unknown
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Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891639.2
First in ClinVar: Jan 31, 2015 Last updated: Dec 09, 2023 |
Geographic origin: Middle East
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Uncertain significance
(Feb 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: SCV000913646.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 62 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with histidine at codon 62 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 26621581, 29357934 ) and in a healthy individual as well (PMID: 28659821). This variant has been identified in 15/280762 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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Likely benign
(Nov 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Familial thoracic aortic aneurysm and aortic dissection
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001210350.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
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Uncertain Significance
(Dec 01, 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: SCV004823147.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 62 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with histidine at codon 62 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 26621581, 29357934 ) and in a healthy individual as well (PMID: 28659821). This variant has been identified in 15/280762 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: 18
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Uncertain Significance
(Nov 03, 2022)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000058770.6
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Arg62His variant in FBN1 has been identified in 1 individual with features of Marfan syndrome and 2 individuals with aortic aneurysm or dissection (Regalado … (more)
The p.Arg62His variant in FBN1 has been identified in 1 individual with features of Marfan syndrome and 2 individuals with aortic aneurysm or dissection (Regalado 2016, Becerra-Muñoz 2018, LMM data). It has also been identified in 0.016% (4/24662) of African chromosomes by Genome Aggregation Databse (http://gnomad.broadinstitute.org). Arginine (Arg) at position 62 is not conserved in mammals or evolutionarily distant species and 6 mammals (marmoset, prairie vole, naked mole rat, guinea pig, chinchilla, brush tailed rat) carry a Histidine (His) at this position despite high nearby amino acid conservation, suggesting that this change may be tolerated. In summary, while the clinical significance of the p.Arg62His variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4_Strong, PS4_Supporting. (less)
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Uncertain significance
(Aug 14, 2023)
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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: SCV000919330.2
First in ClinVar: Jun 02, 2019 Last updated: Oct 04, 2023 |
Comment:
Variant summary: FBN1 c.185G>A (p.Arg62His) 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.185G>A (p.Arg62His) 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 6e-05 in 249738 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FBN1 causing Marfan Syndrome (6e-05 vs 0.00011), allowing no conclusion about variant significance. c.185G>A has been reported in the literature in individuals affected with Marfan Syndrome (Lerner-Ellis_2014), isolated Thoracic Aneurism (Becerra-Munoz_2018; Regalado_2016) as well as in healthy individual without any cardiac abnormalities (Gillis_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24793577, 26621581, 29357934, 28659821). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7), likely benign (n=1), or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(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: SCV000883022.1
First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 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 |
Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor. | Gillis E | Frontiers in physiology | 2017 | PMID: 28659821 |
Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections. | Regalado ES | Clinical genetics | 2016 | PMID: 26621581 |
The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). | Lerner-Ellis JP | Molecular genetics and metabolism | 2014 | PMID: 24793577 |
Text-mined citations for rs145942328 ...
HelpRecord last updated Apr 20, 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.