Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002231261 | SCV000629554 | pathogenic | Hereditary hemorrhagic telangiectasia | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change affects codon 437 of the ENG mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ENG protein. This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hemorrhagic telangiectasia (PMID: 9554745). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 458335). 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. This variant disrupts the c.1311G nucleotide in the ENG gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 15517393). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002384068 | SCV002692029 | pathogenic | Cardiovascular phenotype | 2015-08-12 | criteria provided, single submitter | clinical testing | The c.1311G>C pathogenic mutation (also known as p.R437R), located in coding exon 10 of the ENG gene, results from a G to C substitution at nucleotide position 1311. This nucleotide substitution does not change the amino acid at codon 437. However, this change occurs in the last base pair of coding exon 10, which makes it likely to have some effect on normal mRNA splicing. This mutation showed complete segregation in a large kindred of 25 affected individuals with hereditary hemorrhagic telangiectasia (HHT) and was not observed in 115 normal control individuals (Gallione CJ et al. Hum. Mutat., 1998;11:286-94). In addition, other alterations at this nucleotide position, c.1311G>A and c.1311G>T, have also been described in numerous unrelated individuals with HHT and have been predicted to disrupt splicing (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16; McDonald J et al. Clin. Genet., 2011 Apr;79:335-44). Using two different splice site prediction tools, the c.1311G>C 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; however, direct evidence is unavailable. Based on the available evidence, c.1311G>C is classified as a pathogenic mutation. |
| Mayo Clinic Laboratories, |
RCV003480670 | SCV004226804 | likely pathogenic | not provided | 2022-05-04 | criteria provided, single submitter | clinical testing | PP1_strong, PM2_supporting, PVS1_moderate |