Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003989113 | SCV004805878 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 1 | 2024-03-15 | reviewed by expert panel | curation | The NM_001114753.3: c.2T>G variant in ENG may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID:12920067, 32300199, 15024723, ClinVar, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). Four different missense variants, c.3G>A, c.1A>T, c.2T>C, c.1A>G, in the same codon have been classified as pathogenic/likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5_Strong). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PVS1_Strong, PS4, PP4_Moderate, PM5_Strong (specification version 1.0.0; 1/4/2024). |
Invitae | RCV002231266 | SCV000629568 | pathogenic | Hereditary hemorrhagic telangiectasia | 2022-05-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 458346). Disruption of the initiator codon has been observed in individuals with hemorrhagic telangiectasia (PMID: 9554745, 12920067, 15517393, 20414677, 21158752). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ENG mRNA. The next in-frame methionine is located at codon 183. |
Gene |
RCV000579346 | SCV000680678 | pathogenic | not provided | 2021-01-14 | criteria provided, single submitter | clinical testing | Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12920067, 15024723, 9554745, 21158752, 32300199) |