chr9-127826586-C-G

Position:

• chr9-127826586-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4 PS3_Supporting PP3 PP1 PM2_Supporting PP4_Moderate

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: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 2.59

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 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.447G>C	p.Trp149Cys	missense_variant	4/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.447G>C	p.Trp149Cys	missense_variant	4/14		NP_000109.1
ENG	NM_001406715.1	c.447G>C	p.Trp149Cys	missense_variant	4/8		NP_001393644.1
ENG	NM_001278138.2	c.-100G>C		5_prime_UTR_variant	4/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.447G>C	p.Trp149Cys	missense_variant	4/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.447G>C	p.Trp149Cys	missense_variant	4/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-100G>C		5_prime_UTR_variant	4/15	2		ENSP00000479015.1
ENG	ENST00000462196.1	n.347G>C		non_coding_transcript_exon_variant	3/4	3		ENSP00000519251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2025	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) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 08, 2017	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 general population databases (Exome Variant Server, Genome Aggregation Database). The tryptophan at codon 149 is highly conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Trp149Cys: https://www.ncbi.nlm.nih.gov/clinvar/variation/237027/ 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. 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. 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. 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. 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. 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. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 13, 2023	PP3, PM2, PS3, PS4 -

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 06, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	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). -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

-

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

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. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.75
MutPred		0.68		Loss of catalytic residue at L147 (P = 0.0036);Loss of catalytic residue at L147 (P = 0.0036);
MVP		0.97
MPC		1.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.79
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878853657; hg19: chr9-130588865;