ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7606G>A (p.Gly2536Arg) (rs397515854)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Medical Genetics Ghent,University of Ghent RCV000035274 SCV000787344 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000181609 SCV000233912 pathogenic not provided 2018-09-17 criteria provided, single submitter clinical testing p.Gly2536Arg (GGG>AGG): c.7606 G>A in exon 62 of the FBN1 gene (NM_000138.4)The G2536R mutation in the FBN1 gene has been reported in multiple individuals with Marfan syndrome (FBN1-UMD database). Subsequently, G2536R is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. Mutations in nearby residues (C2541F, C2535W) have been reported in association with Marfan syndrome , supporting the functional importance of this region of the protein. Furthermore, the G2536R mutation was not observed in approximately 6500 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, G2536R in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000586498 SCV000695603 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2016-08-05 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.7606G>A (p.Gly2536Arg) variant located in a Ca2+ binding domain causing a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured here due to low reliability) predicting a damaging outcome. The variant of interest was not found in controls (ExAC, 1000 Gs, or ESP). The variant of interest has been reported in multiple affected individuals with varying phenotypes: MFS, MFS-like, and TAAD. In addition, a functional study (Robinson_2012) indicates the variant alterates splicing producing a 32 deletion transcript (<2% total product). Multiple reputable databases/clinical laboratories.Furthermore, mutations in nearby residues (C2541F, C2535W) have been reported in association with Marfan syndrome. Therefore, the variant of interest has been classified as "pathogenic."
Invitae RCV000698696 SCV000827376 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2536 of the FBN1 protein (p.Gly2536Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Marfan syndrome or thoracic aortic aneurysm and/or dissection (TAAD) (PMID: 11524736, 16220557, 17657824, 24793577, 25907466, 26272055) including an occurrence described to be de novo (PMID: 21895641). ClinVar contains an entry for this variant (Variation ID: 42429). Experimental studies have shown that this missense change is associated with the creation of a new splice site, which is predicted to alter RNA splicing and result in a disrupted protein product (PMID: 21895641). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035274 SCV000058922 pathogenic Marfan syndrome 2006-10-28 criteria provided, single submitter clinical testing

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