ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.1686+1G>A

dbSNP: rs1554809228
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506377 SCV000603455 pathogenic not specified 2016-10-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001049940 SCV001214020 pathogenic Hereditary hemorrhagic telangiectasia 2024-02-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the ENG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 16429404, 18673552, 25970827). ClinVar contains an entry for this variant (Variation ID: 439649). 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.
GeneDx RCV001786396 SCV002028839 pathogenic not provided 2021-09-29 criteria provided, single submitter clinical testing Has been identified in a patient with ENG-related phenotype referred for genetic testing at GeneDx, and in the published literature in three individuals from two families with confirmed or suspected HHT (Lux et al., 2013; Heimdal et al., 2016).; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic (ClinVar Variant ID# 439649; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 18673552, 16429404, 23805858, 25970827)
Ambry Genetics RCV002404320 SCV002712550 pathogenic Cardiovascular phenotype 2017-04-17 criteria provided, single submitter clinical testing The c.1686+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the ENG gene. This mutation was identified in an individual with epistaxis, telangiectasias, and pulmonary and cerebral arteriovenous malformations (Lux A et al. Orphanet J Rare Dis, 2013 Jun;8:94). It was also identified in 2 individuals from one Norwegian hereditary hemorrhagic telangiectasia family (Heimdal K et al. Clin. Genet., 2016 Feb;89:182-6). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

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