Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003989110 | SCV004805869 | uncertain significance | Telangiectasia, hereditary hemorrhagic, type 1 | 2024-03-15 | reviewed by expert panel | curation | The NM_001114753.3: c.1961C>G variant in ENG is a missense variant predicted to cause substitution of threonine by serine at amino acid 654 (p.Thr654Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.126, which is below the threshold of less than or equal to 0.15, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). Due to limited evidence, this variant is classified as a variant of uncertain significance 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, BP4 (specification version 1.0.0; 1/4/2024). |
Gene |
RCV000490183 | SCV000576482 | uncertain significance | not specified | 2017-05-03 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the ENG gene. The T654S variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, the T654S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to threonine are tolerated across species and where serine is the wild type in several species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the T654S variant occurs in an alternate transcript where no variants have been reported in the Human Gene Mutation Database in association with HHT or other ENG-related disorders (Stenson et al., 2014). |