ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.2T>G (p.Met1Arg)

dbSNP: rs267606783
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen 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.
GeneDx 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)

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