Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001059848 | SCV001224498 | pathogenic | Hereditary hemorrhagic telangiectasia | 2023-11-15 | 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 individuals with hereditary hemorrhagic telangiectasia (PMID: 15517393). ClinVar contains an entry for this variant (Variation ID: 854739). 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: 9554745, 21158752). 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. |
| ARUP Laboratories, |
RCV001286216 | SCV001472749 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 1 | 2019-12-04 | criteria provided, single submitter | clinical testing | The ENG c.1311G>A; p.Arg437Arg variant is reported in the literature in five individuals affected with hereditary hemorrhagic telangiectasia (HHT) (Letteboer 2005). The five affected individuals with this variant were determined to share a common ancestor in the year 1745 (Letteboer 2005), suggesting the variant has segregated with disease over numerous meioses. The c.1311G>A variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is a synonymous variant in a moderately conserved nucleotide at the end of exon 10, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, although this has not yet been verified by RNA studies. Still, other variants at the same nucleotide (c.1311G>C, c.1311G>T) have been reported in individuals with HHT and are considered disease-causing (Gallione 1998, McDonald 2011), suggesting this position may be intolerant to sequence variation. Based on available information, the c.1311G>A variant is considered to be pathogenic. References: Gallione CJ et al. Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles. Hum Mutat. 1998;11(4):286-94. Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. |
| Ambry Genetics | RCV002379579 | SCV002693622 | pathogenic | Cardiovascular phenotype | 2018-04-09 | criteria provided, single submitter | clinical testing | The c.1311G>A variant (also known as p.R437R), located in coding exon 10 of the ENG gene, results from a G to A substitution at nucleotide position 1311. This nucleotide substitution does not change the 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 was detected in multiple individuals meeting clinical diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT) (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16). In addition, other alterations at this nucleotide position, c.1311G>C and c.1311G>T, have also been described in numerous unrelated individuals with HHT (Gallione CJ et al. Hum. Mutat., 1998;11:286-94; McDonald J et al. Clin. Genet., 2011 Apr;79:335-44). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |