rs878853657
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3_SupportingPP4_ModeratePP3PP1PM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.447G>C variant in ENG is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 149 (p.Trp149Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID:9554745, 22022569, 22991266, 32300199, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with HHT in 3 affected individuals of a family (4 generations) (PP1; PMID:10545596). The computational predictor REVEL gives a score of 0.762, which is above the threshold of ≥0.644, evidence that correlates with impact to ENG function (PP3). Additionally, expression studies in endoglin-deficient mice, human umbilical vein endothelial cells (HUVECs) and peripheral blood activated monocytes showed reduced expression of fully processed normal endoglin indicating that this variant impacts protein function (PS3_Supporting; PMID:10545596, 11343967, 10749981). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PP3, PP4_Moderate, PS4, PS3_Supporting, PP1 (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10582615/MONDO:0008535/136
Frequency
Consequence
NM_001114753.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ENG | NM_001114753.3 | c.447G>C | p.Trp149Cys | missense_variant | Exon 4 of 15 | ENST00000373203.9 | NP_001108225.1 | |
| ENG | NM_000118.4 | c.447G>C | p.Trp149Cys | missense_variant | Exon 4 of 14 | NP_000109.1 | ||
| ENG | NM_001406715.1 | c.447G>C | p.Trp149Cys | missense_variant | Exon 4 of 8 | NP_001393644.1 | ||
| ENG | NM_001278138.2 | c.-100G>C | 5_prime_UTR_variant | Exon 4 of 15 | NP_001265067.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ENG | ENST00000373203.9 | c.447G>C | p.Trp149Cys | missense_variant | Exon 4 of 15 | 1 | NM_001114753.3 | ENSP00000362299.4 | ||
| ENG | ENST00000344849.4 | c.447G>C | p.Trp149Cys | missense_variant | Exon 4 of 14 | 1 | ENSP00000341917.3 | |||
| ENG | ENST00000480266.6 | c.-100G>C | 5_prime_UTR_variant | Exon 4 of 15 | 2 | ENSP00000479015.1 | ||||
| ENG | ENST00000462196.1 | n.347G>C | non_coding_transcript_exon_variant | Exon 3 of 4 | 3 | ENSP00000519251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:3
The NM_001114753.3: c.447G>C variant in ENG is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 149 (p.Trp149Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID: 9554745, 22022569, 22991266, 32300199, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with HHT in 3 affected individuals of a family (4 generations) (PP1; PMID: 10545596). The computational predictor REVEL gives a score of 0.762, which is above the threshold of greater than or equal to 0.644, evidence that correlates with impact to ENG function (PP3). Additionally, expression studies in endoglin-deficient mice, human umbilical vein endothelial cells (HUVECs) and peripheral blood activated monocytes showed reduced expression of fully processed normal endoglin indicating that this variant impacts protein function (PS3_Supporting; PMID: 10545596, 11343967, 10749981). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PP3, PP4_Moderate, PS4, PS3_Supporting, PP1 (specification version 1.0.0; 1/4/2024). -
The ENG c.447G>C; p.Trp149Cys variant (rs878853657) has been reported in several individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) and has been shown to segregate with disease in a four generation family (Bossler 2006, Bourdeau 2000, Gallione 2000, McDonald 2011, Nishida 1999). In addition, functional assays show the missense variant results in reduced expression of fully processed normal endoglin (Bourdeau 2000, Lux 2000, Pece-Barbara 1999). This variant is reported as pathogenic in ClinVar (Variation ID: 237027), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The tryptophan at codon 149 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.762). Based on available information, this variant is considered to be pathogenic. References: 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. PMID: 16752392. Bourdeau A et al. Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1. Am J Pathol. 2000 Mar;156(3):911-23. PMID: 11343967. Gallione CJ et al. Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles. Hum Mutat. 1998;11(4):286-94. PMID: 9554745. Lux A et al. Expression analysis of endoglin missense and truncation mutations: insights into protein structure and disease mechanisms. Hum Mol Genet. 2000 Mar 22;9(5):745-55. PMID: 10749981. 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 Apr;79(4):335-44. PMID: 21158752. McDonald J et al. Curacao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). Genet Med. 2020 Jul;22(7):1201-1205. PMID: 32300199. 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. PMID: 22991266. Pece-Barbara N et al. Expression analysis of four endoglin missense mutations suggests that haploinsufficiency is the predominant mechanism for hereditary hemorrhagic telangiectasia type 1. Hum Mol Genet. 1999 Nov;8(12):2171-81. PMID: 10545596. -
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not provided Pathogenic:2
Functional studies indicate that, in the presence of W149C, trafficking of the ENG-encoded protein to the cell membrane is inhibited, and dimerization with wild-type protein likely results in a dominant-negative effect (PMID: 10749981, 10545596, 22022569, 25080347); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12667943, 9554745, 22022569, 20414677, 25080347, 16611099, 10545596, 16690726, 16752392, 10702408, 21158752, 32300199, 10749981, 22991266) -
PP3, PM2, PS3, PS4 -
See cases Pathogenic:1
The ENG p.Trp149Cys variant has been reported in several individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) and has been shown to segregate within families (PMID: 16752392, PMID: 10702408, PMID: 9554745, PMID: 21158752, PMID: 22991266). This variant is absent from population databases (gnomAD and ExAC frequencies of zero). -
ENG-related disorder Pathogenic:1
The ENG c.447G>C variant is predicted to result in the amino acid substitution p.Trp149Cys. This variant was reported in individuals with hereditary hemorrhagic telangiectasia (McDonald et al. 2020. PubMed ID: 32300199). This variant has been reported to co-segregate with disease in several families (Nishida et al. 2012. PubMed ID: 22991266; Bourdeau et al. 2000. PubMed ID: 10702408). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.W149C pathogenic mutation (also known as c.447G>C), located in coding exon 4 of the ENG gene, results from a G to C substitution at nucleotide position 447. The tryptophan at codon 149 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was identified in three individuals of a multi-generational hereditary hemorrhagic telangiectasia (HHT) family presenting with epistaxis, telangiectasias, and pulmonary arteriovenous malformations (Bourdeau A et al. Am. J. Pathol., 2000 Mar;156:911-23). In another study, this mutation was identified in five individuals from three HHT families (Nishida T et al. Am. J. Med. Genet. A, 2012 Nov;158A:2829-34). Studies of monocytes isolated from one individual with p.W149C showed reduced levels of fully glycosylated endoglin (Pece-Barbara N et al. Hum. Mol. Genet., 1999 Nov;8:2171-81). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Hereditary hemorrhagic telangiectasia Pathogenic:1
This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 149 of the ENG protein (p.Trp149Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 9554745, 16690726, 20414677, 21158752, 22991266). ClinVar contains an entry for this variant (Variation ID: 237027). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ENG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ENG function (PMID: 10545596, 10749981, 25080347). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at