Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001289855 | SCV001477854 | likely pathogenic | Telangiectasia, hereditary hemorrhagic, type 1 | 2019-10-21 | criteria provided, single submitter | clinical testing | The ENG c.1645T>G; p.Cys549Gly variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 549 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, two different variants at this codon (Cys549Arg, Cys549Tyr) have been identified by our laboratory in multiple individuals affected with HHT and are considered to be pathogenic, giving further support of the importance of this residue. Based on available information, the p.Cys549Gly variant is considered to be likely pathogenic. |
| Victorian Clinical Genetics Services, |
RCV001289855 | SCV002768783 | uncertain significance | Telangiectasia, hereditary hemorrhagic, type 1 | 2020-05-04 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a cysteine to a glycine (exon 12). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (Zona pellucida domain; Alt, A., et al. (2012)) (N) 0704 - Comparable variant has low previous evidence for pathogenicity (ClinVar, McDonald, J., et al. (2011, Richards-Yutz, J., et al. (2010)) (P) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
| Invitae | RCV003759041 | SCV004462047 | pathogenic | Hereditary hemorrhagic telangiectasia | 2023-05-02 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys549 amino acid residue in ENG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20414677, 21158752; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 995686). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 549 of the ENG protein (p.Cys549Gly). |