Submissions for variant NM_000138.5(FBN1):c.2147G>A (p.Gly716Glu)

dbSNP: rs794728185

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181453	SCV000233755	likely pathogenic	not provided	2013-08-05	criteria provided, single submitter	clinical testing	p.Gly716Glu (GGA>GAA): c.2147 G>A in exon 18 of the FBN1 gene (NM_000138.4) The Gly716Glu variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly716Glu results in a non-conservative amino acid substitution of non-polar Glycine with a negatively charged Glutamic acid at a position that is conserved across species. In silico analysis predicts Gly716Glu is damaging to the protein structure/function. Mutations in nearby residues (Cys711Tyr, Gly721Cys, Asp723Val, Asp723Ala, Ile724Val, Ile724Arg) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Gly716Glu variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, while Gly716Glu is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant.The variant is found in TAAD panel(s).
Invitae	RCV000536158	SCV000627850	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-08-27	criteria provided, single submitter	clinical testing	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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 716 of the FBN1 protein (p.Gly716Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 199989).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622454	SCV000740515	likely pathogenic	Marfan syndrome	2017-06-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323430	SCV004030036	uncertain significance	not specified	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2147G>A (p.Gly716Glu) results in a non-conservative amino acid change located in the TGF-beta binding protein domain (Baudhuin_2019) 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 251490 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowlege, c.2147G>A has not been reported in the literature in individuals affected with Marfan Syndrome and no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 31227806). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely pathogenic, however without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
New York Genome Center	RCV000622454	SCV004176052	likely pathogenic	Marfan syndrome	2023-05-23	criteria provided, single submitter	clinical testing	The c.2147G>A variant in FBN1 has not previously been reported in the literature and it has been deposited in ClinVar [ClinVar ID: 199989] as Likely Pathogenic with respect to Marfan syndrome. The c.2147G>A variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.2147G>A variant in FBN1 is located in exon 18 of this 66-exon gene and predicted to replace an evolutionarily conserved glycine amino acid with glutamic acid at position 716 of the encoded protein. In silico predictions are in favor of damaging effectfor p.(Gly716Glu) variant's effect [(CADD v1.6 = 24.1, REVEL = 0.645)]; however, there are no functional studies to support or refute these predictions. Variants nearby p.(Gly716) residue within the kinase domain have been reported in the literature [PMID: 18435798] in individuals with Marfan syndrome. Based on available evidence this c.2147G>A p.(Gly716Glu) variant identified in FBN1 is classified as Likely Pathogenic.