Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001979778 | SCV002221006 | likely pathogenic | Hereditary hemorrhagic telangiectasia | 2023-12-23 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 7 of the ENG gene. It does not directly change the encoded amino acid sequence of the ENG protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1447355). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV002386800 | SCV002695854 | pathogenic | Cardiovascular phenotype | 2019-05-01 | criteria provided, single submitter | clinical testing | The c.991+4A>G intronic pathogenic mutation results from an A to G substitution 4 nucleotides after coding exon 7 in the ENG gene. This mutation co-segregated with hereditary hemorrhagic telangiectasia in one family tested in our laboratory. This pathogenic variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder. In addition, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |