Submissions for variant NM_000138.5(FBN1):c.6007G>A (p.Gly2003Arg)

gnomAD frequency: 0.00002  dbSNP: rs1413737899

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002237	SCV001160112	uncertain significance	not specified	2018-11-15	criteria provided, single submitter	clinical testing	The FBN1 c.6007G>A; p.Gly2003Arg variant is reported in the literature in at least one individual affected with severe adolescent idiopathic scoliosis (Buchan 2014). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 2003 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Other computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site, but the effects on splicing are unknown. Due to limited information, the clinical significance of the p.Gly2003Arg variant is uncertain at this time. References: Buchan JG et al. Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. Hum Mol Genet. 2014 Oct 1;23(19):5271-82.
Color Diagnostics, LLC DBA Color Health	RCV001190656	SCV001358209	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 2003 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 are inconclusive regarding the impact of this variant on RNA splicing. A functional study has shown that the mutant protein perturbs TGF-Beta signaling pathway (PMID: 31774634). This variant has been reported in an individual affected with adolescent idiopathic scoliosis (PMID: 24833718, 26333736). This variant has not been identified 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.
Invitae	RCV001316848	SCV001507487	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2003 of the FBN1 protein (p.Gly2003Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adolescent idiopathic scoliosis (PMID: 24833718). ClinVar contains an entry for this variant (Variation ID: 811830). 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. Experimental studies have shown that this missense change affects FBN1 function (PMID: 31774634). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Institute of Human Genetics, University Hospital Muenster	RCV002287456	SCV002577789	uncertain significance	See cases	2021-12-08	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PP3,BP1
Fulgent Genetics, Fulgent Genetics	RCV002479194	SCV002790518	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	2021-11-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004471	SCV004814612	uncertain significance	Marfan syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 2003 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 are inconclusive regarding the impact of this variant on RNA splicing. A functional study has shown that the mutant protein perturbs TGF-beta- signaling pathway (PMID: 31774634). This variant has been reported in an individual affected with adolescent idiopathic scoliosis (PMID: 24833718, 26333736). This variant has not been identified 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.
Ambry Genetics	RCV001190656	SCV005032433	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-02-09	criteria provided, single submitter	clinical testing	The p.G2003R variant (also known as c.6007G>A), located in coding exon 48 of the FBN1 gene, results from a G to A substitution at nucleotide position 6007. The glycine at codon 2003 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported in an adolescent idiopathic scoliosis cohort (Buchan JG et al. Hum Mol Genet, 2014 Oct;23:5271-82). This alteration may have an impact on protein function (Lin M et al. Mol Genet Genomic Med, 2020 Jan;8:e1023). 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 available evidence, the clinical significance of this alteration remains unclear.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001724206	SCV001957353	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001724206	SCV001973976	likely pathogenic	not provided		no assertion criteria provided	clinical testing