ClinVar Genomic variation as it relates to human health

The c.1080_1083delGACA pathogenic variant in the ENG gene, also reported as c.1078_1081delGACA due to alternate nomenclature, has been identified previously in multiple members of a large family with HHT (Gallione et al., 1998). It has also been identified in several other unrelated individuals with HHT (Wehner et al., 2006; Bossler wt al., 2006; Olivieri et al., 2007; Nishida et al., 2012). Additionally, the c.1080_1083delGACA variant has not been observed in large population cohorts (Lek et al., 2016). The c.1080_1083delGACA variant causes a shift in reading frame starting at codon threonine 361, changing it to a serine, and creating a premature stop codon at position 7 of the new reading frame, denoted p.Thr361SerfsX7. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, other frameshift variants in the ENG gene have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene.

This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 9554745, 16542389, 17786384, 21158752, 22991266). ClinVar contains an entry for this variant (Variation ID: 213214). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr361Serfs*7) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500).

PVS1+PM2+PP4

PVS1, PS4, PP1_Strong, PM2, PP4

The ENG c.1080_1083delGACA; p.Thr361SerfsTer7 variant (rs863223540), also reported as c.1078_1081del, is reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (HHT) (Gallione 1998, Nishida 2012, Snellings 2019). This variant is also reported in ClinVar (Variation ID: 213214). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this 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. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34. Snellings DA et al. Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1. Am J Hum Genet. 2019 Nov 7;105(5):894-906.

The c.1080_1083delGACA pathogenic mutation, located in coding exon 8 of the ENG gene, results from a deletion of 4 nucleotides at nucleotide positions 1080 to 1083, causing a translational frameshift with a predicted alternate stop codon (p.T361Sfs*7). This mutation has been identified in multiple individuals with epistaxis, telangiectasias, and pulmonary arteriovenous malformations (Gallione CJ et al. Hum. Mutat., 1998;11:286-94; Wehner LE et al. Clin. Genet., 2006 Mar;69:239-45; Lee NP et al. J. Med. Genet., 2011 May;48:353-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.