ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1134G>A (p.Ala378=) (rs1329127701)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001034649 SCV000629546 pathogenic Hereditary hemorrhagic telangiectasia 2020-10-19 criteria provided, single submitter clinical testing 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 of the ENG coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and in a family affected with hereditary hemorrhagic telangiectasia (HHT) (PMID: 15517393, 17786384, 24196379, 20414677). This variant is also known as IVS8 ds G-A -1 and as A374A in the literature. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098) but according to multiple splice site algorithms, this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. In summary, this change is absent from population databases, has been reported in several affected individuals and is expected to affect splicing of the ENG mRNA. For these reasons it has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000530058 SCV001158632 pathogenic Hereditary hemorrhagic telangiectasia type 1 2019-07-01 criteria provided, single submitter clinical testing 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000530058 SCV001439429 likely pathogenic Hereditary hemorrhagic telangiectasia type 1 2018-01-01 criteria provided, single submitter research PM2++PP3+ PP4+PP5
GeneDx RCV001545412 SCV001764739 uncertain significance not provided 2020-11-12 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar (ClinVar Variant ID# 458328; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32503579, 16752392, 32303606, 20414677, 17786384, 24196379, 15517393)

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