ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.1273-2A>G (rs373842615)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256118 SCV000322194 pathogenic not provided 2016-04-07 criteria provided, single submitter clinical testing The c.1273-2 A>G pathogenic variant has been reported in one individual with a clinical diagnosis of HHT who presented with pulmonary arteriovenous malformations (AVMs), epistaxis, telangiectasias and a positive family history (Bossler et al., 2006); however, no additional information regarding other affected family members was provided. This variant destroys the canonical splice acceptor site in intron 9 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Many other downstream splice site variants in the ENG gene have been reported in HGMD in association with HHT (Stenson et al., 2014). Furthermore, the c.1273-2 A>G variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.1273-2 A>G in the ENG gene is interpreted as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508197 SCV000603480 pathogenic not specified 2017-03-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV000679898 SCV000807322 pathogenic Hereditary hemorrhagic telangiectasia type 1 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory maternally inherited in a 2-year-old male with bloody vomit and poor gut motility, in addition to motor delays, short stature microcephly, polymicrogyria vs. cortical malformation.
Invitae RCV000791417 SCV000814864 pathogenic Hereditary hemorrhagic telangiectasia 2020-10-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 of the ENG gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs373842615, ExAC 0.002%). This variant has been observed in individuals affected with ENG-related disease (PMID: 16752392, Invitae). ClinVar contains an entry for this variant (Variation ID: 162498). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). For these reasons, this variant has been classified as Pathogenic.
CSER _CC_NCGL, University of Washington RCV000149883 SCV000190185 pathogenic Haemorrhagic telangiectasia 1 2014-06-01 no assertion criteria provided research

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