ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.2953G>A (p.Gly985Arg)
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
-
NM_000138.5(FBN1):c.2953G>A (p.Gly985Arg)
Variation ID: 200008 Accession: VCV000200008.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q21.1 15: 48489980 (GRCh38) [ NCBI UCSC ] 15: 48782177 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 28, 2024 Sep 8, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000138.5:c.2953G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Gly985Arg missense NC_000015.10:g.48489980C>T NC_000015.9:g.48782177C>T NG_008805.2:g.160809G>A LRG_778:g.160809G>A LRG_778t1:c.2953G>A LRG_778p1:p.Gly985Arg - Protein change
- G985R
- Other names
- p.G985R:GGG>AGG
- Canonical SPDI
- NC_000015.10:48489979:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 2, 2019 | RCV000181473.12 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 8, 2023 | RCV000549578.17 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 21, 2017 | RCV000586105.8 | |
Likely pathogenic (1) |
no assertion criteria provided
|
Nov 7, 2017 | RCV000663591.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 1, 2018 | RCV001374767.8 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 8, 2023 | RCV002310746.9 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jun 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695500.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The FBN1 c.2953G>A (p.Gly985Arg) missense variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico … (more)
Variant summary: The FBN1 c.2953G>A (p.Gly985Arg) missense variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools. This variant is located in TB domain and glycines in the FBN1 gene are implicated in correct domain-domain packing (Faive_2009). This variant is absent in 121470 control chromosomes (including ExAC). This variant has been reported in several MFS (classic as well as incomplete MFS) patients. In one family, this variant was found in three affected members with MFS or MFS-like syndrome but not in five unaffected members, indicating cosegregation with disease (Howarth_2007). In two other families, probands affected with classic MFS and two first-degree relatives in each family carried the variant; however affected status of the family members was not clearly indicated (Ware_2016). In contrast to the pathogenic outcome from these three families, a study reclassified this variant to benign from family segregation analysis (Yang_2016). However, genotypic and phenotypic details of family members were not provided, limiting independent evaluation of the evidences. Two clinical diagnostic laboratories (via ClinVar) have classified this variant as likely pathogenic (one has noted the finding of Yang_2016). Another missense change at the same residue G985E has also been reported in a patient with MFS, suggesting that Gly985 codon could be mutational hot-spot. Based on the currently available data, this variant is classified as likely pathogenic. (less)
|
|
Likely pathogenic
(Sep 01, 2018)
|
criteria provided, single submitter
Method: research
|
Isolated thoracic aortic aneurysm
Affected status: yes
Allele origin:
germline
|
Department of Vascular Biology, Beijing Anzhen Hospital
Accession: SCV001439548.1
First in ClinVar: Apr 28, 2021 Last updated: Apr 28, 2021 |
Sex: mixed
|
|
Likely pathogenic
(Dec 02, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000233775.13
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located at a highly conserved Glycine residue in a TB domain, which may be important for protein structure/function (Collod-Beroud et al., 2003); Reported in ClinVar as pathogenic and likely pathogenic (ClinVar Variant ID# 200008; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31098894, 19002209, 19161152, 17627385, 27611364, 16220557, 19863550, 24941995, 27479044, 24199744, 11700157, 29907982, 32123317, 33059708) (less)
|
|
Likely pathogenic
(Mar 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000319440.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.G985R variant (also known as c.2953G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide … (more)
The p.G985R variant (also known as c.2953G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 2953. The glycine at codon 985 is replaced by arginine, an amino acid with dissimilar properties, and is located in the TGFBP #03 domain. This alteration has been identified in multiple individuals with classical Marfan syndrome and reported to co-segregate with disease (Loeys B et al. Arc Intern Med. 2001;161(20):2447-54; Howarth R et al. Genet. Test., 2007;11:146-52; Ware AL et al. Cardiovasc. Pathol. 2016 Jun;25:418-22). Another study has suggested that this alteration does not co-segregate with disease (Yang H et al. Sci Rep, 2016 Sep;6:33002). An alteration affecting the same amino acid (p.G985E, c.2954G>A) has been reported in individuals with classical Marfan syndrome (Collod-Béroud G et al. Am. J. Hum. Genet., 1999 Sep;65:917-21; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Feb 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004240570.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Sep 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Invitae
Accession: SCV000627877.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 985 of the FBN1 protein (p.Gly985Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 985 of the FBN1 protein (p.Gly985Arg). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 200008). This missense change has been observed in individual(s) with Marfan syndrome or FBN1-related conditions (PMID: 11700157, 16220557, 17627385, 19863550, 24199744). This variant is not present in population databases (gnomAD no frequency). (less)
|
|
Likely pathogenic
(Nov 07, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Marfan syndrome
Affected status: yes
Allele origin:
germline
|
Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000786905.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
|
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 |
---|---|---|---|---|
Genetic testing of 248 Chinese aortopathy patients using a panel assay. | Yang H | Scientific reports | 2016 | PMID: 27611364 |
Detection of 15 novel mutations in 52 children from 40 families with the Marfan or Loeys-Dietz syndrome and phenotype-genotype correlations. | Pees C | Clinical genetics | 2014 | PMID: 24199744 |
Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ethnic differences in clinical manifestation. | Yoo EH | Clinical genetics | 2010 | PMID: 19863550 |
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 |
Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype-phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy. | Turner CL | American journal of medical genetics. Part A | 2009 | PMID: 19161152 |
Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation. | Faivre L | European journal of human genetics : EJHG | 2009 | PMID: 19002209 |
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 |
Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome. | Rommel K | Human mutation | 2005 | PMID: 16220557 |
Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. | Loeys B | Human mutation | 2004 | PMID: 15241795 |
Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. | Loeys B | Archives of internal medicine | 2001 | PMID: 11700157 |
Demonstration of the recurrence of Marfan-like skeletal and cardiovascular manifestations due to germline mosaicism for an FBN1 mutation. | Collod-Béroud G | American journal of human genetics | 1999 | PMID: 10441597 |
click to load more click to collapse |
Text-mined citations for rs794728199 ...
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.