ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.776G>A (p.Gly259Glu)

gnomAD frequency: 0.00001  dbSNP: rs751169871
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000773642 SCV000907336 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-05-01 criteria provided, single submitter clinical testing This missense variant replaces glycine with glutamic acid at codon 259 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with Marfan syndrome or aortic aneurysm (PMID: 25907466, ClinVar SCV002254511.2). This variant has been identified in 2/251428 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000812490 SCV000952805 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-01-15 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 259 of the FBN1 protein (p.Gly259Glu). This variant is present in population databases (rs751169871, gnomAD 0.002%). This missense change has been observed in individuals with Marfan syndrome or aortic aneurysm (PMID: 25907466; Invitae). ClinVar contains an entry for this variant (Variation ID: 549428). 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.Gly259 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.
GeneDx RCV001584527 SCV001820321 uncertain significance not provided 2020-06-29 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 549428; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25907466)
Centre of Medical Genetics, University of Antwerp RCV000663976 SCV002025377 uncertain significance Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PP3, PP4
Fulgent Genetics, Fulgent Genetics RCV002507148 SCV002815215 uncertain significance Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome 2021-10-07 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000663976 SCV004823109 uncertain significance Marfan syndrome 2023-12-07 criteria provided, single submitter clinical testing This missense variant replaces glycine with glutamic acid at codon 259 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with Marfan syndrome or aortic aneurysm (PMID: 25907466, ClinVar SCV002254511.2). This variant has been identified in 2/251428 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.
Center for Medical Genetics Ghent, University of Ghent RCV000663976 SCV000787358 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.