Submissions for variant NM_001114753.3(ENG):c.1428+1G>A

dbSNP: rs863223542

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198224	SCV000250089	likely pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22991266, 21158752)
Invitae	RCV000551278	SCV000629556	pathogenic	Hereditary hemorrhagic telangiectasia	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 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 hemorrhagic telangiectasia (PMID: 21158752, 22991266; Invitae). ClinVar contains an entry for this variant (Variation ID: 213216). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001286561	SCV001473155	pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2020-12-30	criteria provided, single submitter	clinical testing	The ENG c.1428+1G>A variant (rs863223542) has been reported in the literature individuals affected with HHT (Nishida 2012, McDonald 2011), as well as identified by our laboratory in several affected individuals. The variant is reported in ClinVar (Variation ID: 213216) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 11, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011;79(4):335-344.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001286561	SCV002496107	pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2021-03-30	criteria provided, single submitter	clinical testing	ENG NM_000118.3 exon 11 c.1428+1G>A: This variant has been reported in the literature in 3 individuals with hereditary hemorrhagic telangiectasia (HHT) (McDonald 2011 PMID:21158752, Nishida 2012 PMID:22991266). This variant is not present in large control databases but is present in ClinVar (Variation ID:213216). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Abdalla 2006 PMID:15879500, Wooderchak 2010 PMID:20412114). In summary, this variant is classified as pathogenic based on the data above.
Ambry Genetics	RCV002390514	SCV002701016	pathogenic	Cardiovascular phenotype	2024-03-08	criteria provided, single submitter	clinical testing	The c.1428+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the ENG gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant was reported in multiple individuals with features consistent with hereditary hemorrhagic telangiectasia (McDonald J, Clin. Genet. 2011;79(4):335-44; Nishida T et al. Am. J. Med. Genet. A. 2012 Nov;158A(11):2829-34). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000198224	SCV004226802	pathogenic	not provided	2023-04-06	criteria provided, single submitter	clinical testing	PP3, PM2_supporting, PS4, PVS1_strong