Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001962621 | SCV002208528 | uncertain significance | Hereditary hemorrhagic telangiectasia | 2021-03-17 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. This variant has not been reported in the literature in individuals with ENG-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with asparagine at codon 168 of the ENG protein (p.Ile168Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. |
| Molecular Genetics, |
RCV002221294 | SCV002498648 | uncertain significance | Telangiectasia, hereditary hemorrhagic, type 1 | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace isoleucine with asparagine at codon 168 of the ENG protein (p.(Ile168Asn)). The isoleucine residue is moderately conserved (100 vertebrates, UCSC), and is located in GDF2 interaction region of the OR2 (N-terminal orphan region) domain (PMID: 28564608). There is a large physicochemical difference between isoleucine and asparagine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.0), and has been reported as a variant of uncertain significance (LOVD). It has been identified in a single index case with a clinical diagnosis of hereditary haemorrhagic telangiectasia (Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS4_Supporting, PM2_Supporting, PP3. |
| Victorian Clinical Genetics Services, |
RCV002221294 | SCV002768051 | uncertain significance | Telangiectasia, hereditary hemorrhagic, type 1 | 2020-10-19 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-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 isoleucine to asparagine (exon 4). (N) 0251 Variant is heterozygous. (N) 0301 Variant is absent from gnomAD. (P) 0502 Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0604 Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 No comparable variants have previous evidence for pathogenicity. (N) 0804 Variant is absent in the population and has previously been described as variant of uncertain significance once (LOVD). (P) 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 |