rs886039506

chr9-127829770-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001114753.3(ENG):c.277C>T(p.Arg93Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ENG NM_001114753.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.96

Genes affected

ENG (HGNC:3349): (endoglin) This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127829770-G-A is Pathogenic according to our data. Variant chr9-127829770-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127829770-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.277C>T	p.Arg93Ter	stop_gained	3/15	ENST00000373203.9
ENG	NM_000118.4	c.277C>T	p.Arg93Ter	stop_gained	3/14
ENG	NM_001406715.1	c.277C>T	p.Arg93Ter	stop_gained	3/8
ENG	NM_001278138.2	c.-270C>T		5_prime_UTR_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.277C>T	p.Arg93Ter	stop_gained	3/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.277C>T	p.Arg93Ter	stop_gained	3/14	1		A2
ENG	ENST00000480266.6	c.-270C>T		5_prime_UTR_variant	3/15	2
ENG	ENST00000462196.1	n.35C>T		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 15, 2021	- -
Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	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. -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PVS1+PM2+PP4 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 28, 2023	PM2_supporting, PS4, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 05, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2022	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) -

Pulmonary arterial hypertension Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

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. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.21	N
MutationTaster	Benign	1.0	A;A;A;D
Vest4		0.92
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886039506; hg19: chr9-130592049;