Submissions for variant NM_000138.5(FBN1):c.7505A>T (p.Asn2502Ile)

dbSNP: rs1555394243

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521613	SCV000616980	likely pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 20591885)
Invitae	RCV000632019	SCV000753122	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2017-11-03	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FBN1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with isoleucine at codon 2502 of the FBN1 protein (p.Asn2502Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526931	SCV001737696	uncertain significance	not specified	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7505A>T (p.Asn2502Ile) results in a non-conservative amino acid change located in the EGF-like domain 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 251212 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7505A>T in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One lab classified the variant as likely pathogenic while two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
Centre of Medical Genetics, University of Antwerp	RCV000663959	SCV002025448	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS6, PP4
Center for Medical Genetics Ghent, University of Ghent	RCV000663959	SCV000787336	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing