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

dbSNP: rs373842615

Total submissions: 8

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 - https://braingeneregistry.wustl.edu/.