Submissions for variant NM_000138.5(FBN1):c.3902G>T (p.Gly1301Val)

dbSNP: rs1566908083

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170778	SCV001333384	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-04-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002240741	SCV002511392	uncertain significance	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3902G>T (p.Gly1301Val) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251358 control chromosomes (gnomAD). c.3902G>T has been reported in the literature as a likely pathogenic variant in one individual with a suspected or confirmed diagnosis of Marfan Syndrome (Baudhuin_2015), and in two individual with Thoracic aortic aneurysm and dissection (Guo_2015, Haskell_2017). The variant was also reported in 2 individuals with Marfan/Incomplete Marfan syndrome phenotypes in the UMD database (http://www.umd.be/FBN1). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV001170778	SCV002623933	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2015-12-31	criteria provided, single submitter	clinical testing	The p.G1301V variant (also known as c.3902G>T), located in coding exon 31 of the FBN1 gene results from a G to T substitution at nucleotide position 3902. The glycine at codon 1301 is replaced by valine, an amino acid with dissimilar properties, and is located in the cb EGF-like #17 domain. This variant was reported in an individual with thoracic aortic dissection (Guo J et al, Sci Rep 2015 ; 5:13115). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae	RCV002559637	SCV003442965	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1301 of the FBN1 protein (p.Gly1301Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 26272055, 28611029; Invitae). ClinVar contains an entry for this variant (Variation ID: 915682). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003319444	SCV004023926	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	Has been reported in individuals with TAAD and Marfan syndrome (Baudhuin et al., 2015; Guo et al., 2015; Haskell et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26272055, 25652356, 33735269, 28611029)