Submissions for variant NM_001114753.3(ENG):c.277C>T (p.Arg93Ter)

dbSNP: rs886039506

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255761	SCV000322196	pathogenic	not provided	2022-08-16	criteria provided, single submitter	clinical testing	Reported in multiple unrelated individuals diagnosed with HHT from several ethnic backgrounds (Cymerman et al., 2000; Letteboer et al., 2005; Lesca et al., 2006; Olivieri et al., 2006; Gedge et al., 2007; Olivieri et al., 2007; Lee et al., 2009; Nishida et al., 2012; Canzonieri et al., 2014); Observed in a grandmother with pulmonary arteriovenous malformation and reduced levels of ENG-protein in activated peripheral blood monocytes; her unaffected son and grandson demonstrated normal ENG-protein levels in activated peripheral blood monocytes (Cymerman et al., 2000); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16540754, 12673790, 21158752, 31727138, 32503579, 32581362, 32573726, 16752392, 16705692, 17384219, 17786384, 25525159, 15879500, 23801935, 23805858, 25970827, 22991266, 23722869, 19270816, 15517393, 29650961, 32514857, 15521985, 10625079)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791375	SCV000629567	pathogenic	Hereditary hemorrhagic telangiectasia	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg93*) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 10625079, 15517393, 15521985, 16705692, 19270816, 21158752, 22991266, 23722869). ClinVar contains an entry for this variant (Variation ID: 265371). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255761	SCV000885362	pathogenic	not provided	2018-01-05	criteria provided, single submitter	clinical testing	The ENG c.277C>T; p.Arg93Ter variant (rs886039506) has been reported in multiple unrelated families with hereditary hemorrhagic telangiectasia (Bossler 2006, Brusgaard 2004, Cymerman 2000, Gedge 2007, Lesca 2006, Letteboer 2005, Nishida 2012, Olivieri 2007, see HHT ENG database link). This variant is reported as pathogenic in ClinVar (Variation ID: 265371), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database). This variant introduces an early termination codon and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg93Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/265371/ Link to HHT ENG database: http://arup.utah.edu/database/ENG/ENG_display.php Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 Jul;27(7):667-75. Brusgaard K et al. Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2004 Dec;66(6):556-61. Cymerman U et al. Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression and mutation analysis of endoglin. Pediatr Res. 2000 Jan;47(1):24-35. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. Lesca G et al. Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat. 2006 Jun;27(6):598. Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. 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. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52(10):820-9.
Fulgent Genetics, Fulgent Genetics	RCV000545627	SCV000893794	pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2021-11-15	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000545627	SCV001439445	pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2018-01-01	criteria provided, single submitter	research	PVS1+PM2+PP4
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000545627	SCV002557300	pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2022-06-24	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 haemorrhagic telangiectasia, type 1 (HHT; MIM#187300). (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 variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with HHT and regarded as pathogenic (ClinVar, LOVD, PMID: 33919892). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002436090	SCV002747259	pathogenic	Cardiovascular phenotype	2021-09-17	criteria provided, single submitter	clinical testing	The p.R93* pathogenic mutation (also known as c.277C>T), located in coding exon 3 of the ENG gene, results from a C to T substitution at nucleotide position 277. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation was originally identified in an individual with a pulmonary arteriovenous malformation and reduced level of endoglin (Cymerman U et al. Pediatr. Res., 2000 Jan;47:24-35). In one study, this mutation was identified in two individuals who both had epistaxis, pulmonary arteriovenous malformations, and gastrointestinal telangiectasias (Canzonieri C et al. Genet. Med., 2014 Jan;16:3-10). In other studies, this mutation was identified in an individual with recurrent epistaxis, pulmonary and hepatic arteriovenous malformations, telangiectasias, and a positive family history as well as in an individual with pulmonary arterial hypertension (PAH) (Gräf S et al. Nat Commun, 2018 Apr;9:1416; Lee ST et al. J. Korean Med. Sci., 2009 Feb;24:69-76). In a study of Norwegian families with hereditary hemorrhagic telangiectasia, this mutation was identified in twelve individuals from five families (Heimdal K et al. Clin. Genet., 2016 Feb;89:182-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000255761	SCV004226824	pathogenic	not provided	2023-04-28	criteria provided, single submitter	clinical testing	PM2_supporting, PS4, PVS1
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000255761	SCV005197822	pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003750	SCV001162193	pathogenic	Pulmonary arterial hypertension		no assertion criteria provided	research
deCODE genetics, Amgen	RCV000545627	SCV004022113	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2023-07-21	no assertion criteria provided	research	The variant NM_001114753.3:c.277C>T (chr9:127829770) in ENG was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.