Submissions for variant NM_000138.5(FBN1):c.1846G>A (p.Glu616Lys)

dbSNP: rs397515764

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035128	SCV000058768	uncertain significance	not specified	2019-03-07	criteria provided, single submitter	clinical testing	The p.Glu616Lys variant has been reported in an individual meeting Ghent clinical criteria for Marfan syndrome (Stheneur 2009) and is reported in ClinVar (Variation ID: 42294). In addition, this variant has been identified by our laboratory in 2 individuals. In one family it segregated with 2 affected individuals; however, in the other family it was absent in two affected first degree relatives. This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2; PP3;PP4.
Invitae	RCV000459707	SCV000544913	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 616 of the FBN1 protein (p.Glu616Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 12938084, 19293843; Invitae). ClinVar contains an entry for this variant (Variation ID: 42294). 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.Glu616 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 10464652), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000493016	SCV000583182	likely pathogenic	not provided	2020-11-13	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32123317, 19293843, 12938084)
Ambry Genetics	RCV002313726	SCV000738854	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-12-22	criteria provided, single submitter	clinical testing	The p.E616K variant (also known as c.1846G>A), located in coding exon 15 of the FBN1 gene, results from a G to A substitution at nucleotide position 1846. The glutamic acid at codon 616 is replaced by lysine, an amino acid with similar properties, and is located in the cb EGF-like #06 domain. This alteration was reported in a case of familial Marfan syndrome; however, clinical details were limited (Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8). Another alteration affecting the same amino acid, p.E616G (c.1847A>G), has also been reported in association with Marfan syndrome (Liu WO et al. Genet. Test. 1997/98;1:237-42). 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 alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307372	SCV000919345	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2022-10-03	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1846G>A (p.Glu616Lys) results in a conservative amino acid change located in the EGF-like calcium-binding domains (IPR001881) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251434 control chromosomes. c.1846G>A has been reported in the literature in individuals affected with Marfan Syndrome (example: Stheneur_2009, Lerner-Ellis_2014, Zhang_2021 and Li_2021 etc.). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=3), Likely pathogenic (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277117	SCV002566510	uncertain significance	Connective tissue disorder	2022-04-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV002313726	SCV003837682	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-10-19	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000663503	SCV000786803	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing