ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.1429-1G>A

dbSNP: rs2131876244
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV001507758 SCV001713504 likely pathogenic not provided 2020-07-08 criteria provided, single submitter clinical testing PVS1_Strong, PM2
Genetic Services Laboratory, University of Chicago RCV001507758 SCV002069191 pathogenic not provided 2018-06-07 criteria provided, single submitter clinical testing DNA sequence analysis of the ENG gene demonstrated a sequence change in the canonical splice acceptor site of intron 11, c.1429-1G>A. This pathogenic sequence change has previously been described in a patient with features of hereditary hemorrhagic telangiectasia (HHT) (PMID: 21158752). A different sequence change at this nucleotide position (c.1429-1G>C) has also been described in patients with HHT (PMIDs: 21158752, 15880681). This pathogenic sequence change is predicted to affect normal splicing of the ENG gene and result in an abnormal protein. This sequence change is the likely cause of the indicated phenotype, however functional studies have not been performed to prove this conclusively.
Molecular Genetics, Royal Melbourne Hospital RCV002225135 SCV002503803 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2023-03-30 criteria provided, single submitter clinical testing This sequence change affects the canonical acceptor splice site in intron 11 of ENG. It is expected to disrupt RNA splicing and likely results in an absent protein product, or exon 12 skipping with reading frame preservation. Removing exon 12 would remove the majority of the ZP-C domain, which is integral to the proteins function through its interaction with BMP9 (PMID: 28564608 - PVS1_Strong). RNA analyses have not been performed to confirm the presence of a splicing aberration. The variant is absent in a large population cohort (gnomAD v2.1 - PM2), and has been identified in at least four cases with a confirmed clinical diagnosis of hereditary haemorrhagic telangiectasia (ARUP ENG database, Royal Melbourne Hospital - PS4). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Strong, PS4, PM2.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002225135 SCV002557455 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2020-07-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.2, 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. Many protein-truncating variants have been reported (PMID: 21158752) and missense variants have been shown to result in loss of function and dominant negative effects (PMIDs: 25312062, 25080347). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are uninformative. (I) 0703 - Other canonical splice variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The c.1429-1G>C variant has been reported in patients with epistaxis and telangiectasia (PMIDs: 21158752, 15880681), and c.1429-2A>G has been reported as likely pathogenic in ClinVar. (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported in one patient with hereditary haemorrhagic telangiectasia (PMID: 21158752). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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