ClinVar Miner

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

dbSNP: rs373842615
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Total submissions: 8
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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 Telangiectasia, hereditary hemorrhagic, 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 2023-04-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 162498). Disruption of this splice site has been observed in individuals with ENG-related disease (PMID: 16752392; Invitae). This variant is present in population databases (rs373842615, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 9 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).
Ambry Genetics RCV002371992 SCV002686027 pathogenic Cardiovascular phenotype 2024-02-13 criteria provided, single submitter clinical testing The c.1273-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 10 of the ENG gene. 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; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/238470) total alleles studied. The highest observed frequency was 0.001% (1/107270) of European (non-Finnish) alleles. This variant has been described in patients meeting diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT) (Bossler, 2006; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000679898 SCV002798196 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2021-11-24 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000149883 SCV000190185 pathogenic Haemorrhagic telangiectasia 1 2014-06-01 no assertion criteria provided research
GenomeConnect - Brain Gene Registry RCV000679898 SCV004804573 not provided Telangiectasia, hereditary hemorrhagic, type 1 no assertion provided phenotyping only Variant classified as Pathogenic and reported on 11-19-2020 by USAF Medical Genetics Center. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website -

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