Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics, |
RCV002225172 | SCV002503701 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 1 | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change is a deletion of 1 bp in exon 7 (of 15) of ENG that is predicted to create a premature termination codon at position 358 (p.(Ala312Hisfs*47)). It is expected to result in nonsense mediated decay, and loss of function is a well-established mechanism of disease for this gene (ClinVar). The variant is absent in a large population cohort ( gnomAD v2.1 and v3.0). The variant has been identified in an individual with a clinical diagnosis of hereditary haemorrhagic telangiectasia (Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4_Supporting, PM2_Supporting. |
| Victorian Clinical Genetics Services, |
RCV002225172 | SCV002557852 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 1 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hereditary haemorrhagic telangiectasia type 1 (MIM#187300). Many protein truncating variants have been reported (PMID: 21158752) and missense variants have been shown to result in both loss of function and dominant negative effects (PMIDs: 25312062, 25080347). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 – Other variants predicted to cause NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |