ClinVar Genomic variation as it relates to human health

The ENG c.1134G>A; p.Ala378Ala variant (rs1329127701) is reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (HHT) (Bossler 2006, Komiyama 2014, Letteboer 2005, Olivieri 2007, Richards-Yutz 2010). In addition, this variant has been identified in numerous affected individuals by testing performed at ARUP Laboratories. This variant is present on a single chromosomes (1/31364 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant in a moderately conserved nucleotide which is the last nucleotide in ENG exon 8, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by weakening the nearby canonical donor splice site. Based on available information, this variant is considered to be pathogenic. References: Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 Jul;27(7):667-75. Komiyama M et al. Hereditary hemorrhagic telangiectasia in Japanese patients. J Hum Genet. 2014 Jan;59(1):37-41. Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52(10):820-9. Richards-Yutz J et al. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Hum Genet. 2010 Jul;128(1):61-77.

PM2++PP3+ PP4+PP5

Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 24196379, 17786384, 20414677, 32303606, 16752392, 32503579, 32300199, 32573726, 15517393, 34872578)

The ENG c.1134G>A variant is not predicted to result in an amino acid change (p.=). This variant is located at the last nucleotide position of exon 8 and is predicted to interfere with splicing at the consensus site based on splicing prediction programs. This variant has also been reported in several patients affected with hereditary hemorrhagic telangiectasia (HHT) (Letteboer et al. 2005. PubMed ID: 15517393, Bossler et al. 2006. PubMed ID: 16752392; Olivieri et al. 2007. PubMed ID: 17786384, Komiyama et al. 2014. PubMed ID: 24196379). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-130586583-C-T). Based on this evidence, we interpret this variant as pathogenic.

PP1, PP3, PP5, PM2_supporting, PS4

This sequence change affects codon 378 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 8, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 15517393, 17786384, 20414677, 24196379). This variant is also known as IVS8 ds G-A -1 and as A374A. ClinVar contains an entry for this variant (Variation ID: 458328). 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. For these reasons, this variant has been classified as Pathogenic.

The c.1134G>A variant (also known as p.A378A) is located in coding exon 8 of the ENG gene. This variant results from a G to A substitution at nucleotide position 1134. This nucleotide substitution does not change the alanine at codon 378. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in multiple individuals with clinical diagnoses of hereditary hemorrhagic telangiectasia, including at least one demonstrating low level mosaicism (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16; Olivieri C et al. J. Hum. Genet., 2007 Sep;52:820-9; Richards-Yutz J et al. Hum. Genet., 2010 Jul;128:61-77; Clarke JM et al. J. Med. Genet., 2020;57(12):859-862). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.