ClinVar Genomic variation as it relates to human health

The p.Arg528Cys variant in TGFBR2 has been reported in >5 individuals with Loeys -Dietz syndrome, and occurred de novo in at least 3 of these individuals (Loeys 2005, LeMaire 2007, Stheneur 2008, Frischmeyer-Guerrerio 2013). Additionally, it has also been reported by other clinical laboratories in ClinVar (Variation ID 12512). It was absent from large population studies. In vitro functional studies provide evidence that the p.Arg528Cys variant may impact protein function (Horb elt 2010) and computational prediction tools and conservation analysis suggest t hat the p.Arg528Cys variant may impact the protein. Furthermore, a different pat hogenic variant (p.Arg528His) has been reported in several individuals with Loey s-Dietz syndrome at the same position, supporting this change may not be tolerat ed. In summary, this variant meets criteria to be classified as pathogenic for L oeys-Dietz syndrome in an autosomal dominant manner based upon multiple de novo occurrences, absence from controls, functional and computational evidence and pr esence of another pathogenic variant at the same amino acid position. ACMG/AMP C riteria applied (Richards 2015): PM6_Strong, PM2, PM5, PP3, PS3_Supporting.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Reported in ClinVar as pathogenic (ClinVar Variant ID# 12512; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant results in decreased protein expression and has a dominant-negative effect on TGF-beta induced Smad and ERK signalling (Horbelt et al., 2010); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 33436942, 32352226, 31447099, 21098638, 22734312, 20144264, 18781618, 16928994, 19875893, 15731757, 23884466, 17330129)

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 528 of the TGFBR2 protein (p.Arg528Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Loeys–Dietz syndrome (PMID: 15731757, 18781618, 19875893, 20144264). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12512). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt TGFBR2 function. Experimental studies have shown that this missense change affects TGFBR2 function (PMID: 21098638). This variant disrupts the p.Arg528 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15731757, 18781618, 21098638, 23103230). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The p.R528C pathogenic mutation (also known as c.1582C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1582. The arginine at codon 528 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the protein kinase domain. This alteration has been described in several patients with Loeys-Dietz syndrome, and in some cases, the occurrence was reported to be de novo (Loeys BL et al. Nat. Genet. 2005;37(3):275-81). In a study utilizing functional in vitro analyses, this alteration has demonstrated reduced protein expression and TGFβ signaling resulting from a dominant-negative effect (Horbelt D et al. J Cell Sci. 2010;123(Pt 24):4340-50). Based on the available evidence, p.R528C is classified as a pathogenic mutation.

The TGFBR2 c.1582C>T variant is predicted to result in the amino acid substitution p.Arg528Cys. This variant was detected in multiple individuals with Loeys-Dietz syndrome, including at least 2 de novo occurrences (Loeys et al. 2005. PubMed ID: 15731757, Frischmeyer-Guerrerio et al. 2013. PubMed ID: 23884466, Horbelt et al. 2010. PubMed ID: 21098638, LeMaire et al. 2007. PubMed ID: 17330129; Stheneur et al. 2008. PubMed ID: 18781618, Mariucci et al. 2020. PubMed ID: 32352226). Functional studies suggest this variant affects protein function (Horbelt et al. 2010. PubMed ID: 21098638). Different missense variants affecting this amino acid have been reported in patient with Loeys-Dietz syndrome (p.Arg528His, p.Arg528Pro, Loeys et al. 2005. PubMed ID: 15731757, Almpani et al. 2022. PubMed ID: 34916229, Carmignac et al. 2012. PubMed ID: 23103230, Akazawa et al. 2015. PubMed ID: 26096872). The c.1582C>T variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.