ClinVar Genomic variation as it relates to human health

PM2, PS1, PP1, PP4

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."

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).

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2536 of the FBN1 protein (p.Gly2536Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FBN1-related conditions (PMID: 11524736, 16220557, 17657824, 24793577, 25907466, 26272055). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 42429). 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%. Studies have shown that this missense change results in altered splicing and introduces a premature termination codon (PMID: 21895641). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

The p.G2536R pathogenic mutation (also known as c.7606G>A), located in coding exon 61 of the FBN1 gene, results from a G to A substitution at nucleotide position 7606. The glycine at codon 2536 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in subjects with features of Marfan syndrome and thoracic aortic aneurysm and dissection (TAAD) and has been reported as a de novo occurrence (Comeglio P et al. Hum. Mutat., 2001 Sep;18:251; Rommel K et al. Hum. Mutat., 2005 Dec;26:529-39; Robinson DO et al. Clin. Genet., 2012 Sep;82:223-31; Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6; Proost D et al. Hum. Mutat., 2015 Aug;36:808-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, RNA studies show this alteration has an aberrant impact on splicing (Robinson DO et al. Clin. Genet., 2012 Sep;82:223-31). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.