Submissions for variant NM_001114753.3(ENG):c.1465C>T (p.Gln489Ter)

dbSNP: rs1057521648

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421678	SCV000523923	likely pathogenic	not provided	2016-02-09	criteria provided, single submitter	clinical testing	The Q489X variant in the ENG gene has not been reported as a pathogenic variant nor as a benign variant to our knowledge. Q489X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Multiple other downstream nonsense variants in the ENG gene have been reported in HGMD in association with HHT (Stenson et al., 2014). Furthermore, the Q489X likely pathogenic variant was not observed 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.
Invitae	RCV000808225	SCV000948321	pathogenic	Hereditary hemorrhagic telangiectasia	2021-08-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). This variant has been observed to segregate with hereditary hemorrhagic telangiectasia in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 383511). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln489*) in the ENG gene. It is expected to result in an absent or disrupted protein product.
Molecular Genetics, Royal Melbourne Hospital	RCV002225104	SCV002503791	pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature termination codon at position 489 in exon 12 (of 15) of ENG (p.(Gln489*)). This is predicted to result in an absent or disrupted protein product through nonsense mediated decay. Loss of function is a well established disease mechanism for this gene (PVS1). The variant is absent in a large population cohort (PM2, rs1057521648, gnomAD v2.1.1 and v3). The variant has been reported in two unrelated individuals with a clinical diagnosis of hereditary haemorrhagic telangiectasia (PS4_Moderate, PMID: 20414677, 20719417) and is reported to segregate with disease in an affected family (Invitae, ClinVar). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. The following criteria are met: PVS1, PM2, PS4_Moderate.
Ambry Genetics	RCV002392990	SCV002697458	pathogenic	Cardiovascular phenotype	2021-06-29	criteria provided, single submitter	clinical testing	The p.Q489* pathogenic mutation (also known as c.1465C>T), located in coding exon 12 of the ENG gene, results from a C to T substitution at nucleotide position 1465. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation has been reported in individuals with hereditary hemorrhagic telangiectasia (Richards-Yutz J et al. Hum Genet, 2010 Jul;128:61-77; Corre P et al. Br J Oral Maxillofac Surg, 2011 Jul;49:e9-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002225104	SCV002767224	pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2021-05-06	criteria provided, single submitter	clinical testing	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 Hereditary Hemorrhagic Telangiectasia type 1 (MIM#187300). Loss-of-function variants have been reported, while missense variants have been demonstrated to have both loss of function and dominant negative effects on protein activity (PMID: 25312062). (I). 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported multiple times as pathogenic, and have been observed in many individuals with hereditary hemorrhagic telangiectasia (HHT) (DECIPHER, PMID: 20414677). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and has been observed in several individuals with HHT, or epistaxis and telangiectasia (ClinVar, LOVD, PMID: 20414677, PMID: 20719417). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign