ClinVar Genomic variation as it relates to human health

This sequence change in ENG occurs within the canonical splice donor site (+ 2) of intron 10. It is predicted to cause skipping of biologically relevant-exon 10, resulting in an in-frame deletion (removes amino acids 425-437) that is expected to escape nonsense-mediated decay and remove <10% of the protein. The region of the Zona Pellucida domain removed is expected to be critical to protein function because multiple pathogenic variants altering this splice site have been reported (c.1311+2T>A, c.1311+2T>G, c.1311G>C, c.1311G>A; ARUP ENG database; PMID: 9554745, 10625079, 15517393). This variant is absent from the population database gnomAD v2.1 and v3.1. It has been reported in at least two probands with a clinical diagnosis of hereditary haemorrhagic telangiectasia (PMID: 16752392; internal laboratory data). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PS4_Moderate, PM2_Supporting.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with type 1 hereditary haemorrhagic telangiectasia (MIM#187300). Pathogenic missense variants have been demonstrated to have dominant negative and loss of function effects while premature termination variants are associated with a loss of function mechanism (PMIDs: 2508034, 25312062). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0600 - Variant is predicted to disrupt the Zona pellucida-like domain (DECIPHER). (I) 0701 - Other canonical splice site variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. c.1311+2T>G, c.1311+2T>A, c.1311+1G>A and c.1311+1G>C have been reported as pathogenic by clinical laboratories (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with hereditary haemorrhagic telangiectasia (PMIDs: 16752392, 34872578). It has also been reported as pathogenic by a clinical laboratory (ClinVar). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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. Disruption of this splice site has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 16752392, 21158752). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 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).