Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002405785 | SCV002709524 | likely pathogenic | Cardiovascular phenotype | 2021-12-02 | criteria provided, single submitter | clinical testing | The p.C53R variant (also known as c.157T>C), located in coding exon 2 of the ENG gene, results from a T to C substitution at nucleotide position 157. The cysteine at codon 53 is replaced by arginine, an amino acid with highly dissimilar properties. This variant was reported in eight family members with hereditary hemorrhagic telangiectasia (HHT) (Gallione et al. Hum Mutat. 1998;11(4):286-94). In another study this variant was reported in one family with milder symptoms (Bayrac-Toydemir et al. Am J Med Genet A. 2006;140(5):463-70). Multiple studies have reported this alteration causes reduced expression of normal endoglin at the cell surface (Pece-Barbara et. al. Hum Mol Genet. 1999;8(12):2171-81, Ali et al. PLoS One. 2011; 6(10):e26206, Llorca et al. J Mol Biol. 2007;365(3):694-705). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV003759685 | SCV004550593 | pathogenic | Hereditary hemorrhagic telangiectasia | 2023-10-28 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 53 of the ENG protein (p.Cys53Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 9554745, 32300199). ClinVar contains an entry for this variant (Variation ID: 1775674). 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 ENG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ENG function (PMID: 22022569). For these reasons, this variant has been classified as Pathogenic. |