chr9-127825722-A-G

Position:

• chr9-127825722-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS4 PS3_Supporting PM2_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.662T>C variant in ENG is a missense variant predicted to cause substitution of leucine by proline at amino acid 221 (p.Leu221Pro). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID:10545596, 15880681, 17384219, 18498373, 20414677, 22991266, 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 computational predictor REVEL gives a score of 0.478, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, protein expression assays in cell lines showed the variant causes reduced endoglin expression (PS3_Supporting; PMID:10545596). In summary, this variant meets the criteria to be classified as likely 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: PS4, PP4_Moderate, PS3_Supporting, PM2_Supporting (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA374983528/MONDO:0008535/136

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 1.99

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 Likely_pathogenic. Variant got 8 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.
• 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.662T>C	p.Leu221Pro	missense_variant	5/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.662T>C	p.Leu221Pro	missense_variant	5/14		NP_000109.1
ENG	NM_001278138.2	c.116T>C	p.Leu39Pro	missense_variant	5/15		NP_001265067.1
ENG	NM_001406715.1	c.662T>C	p.Leu221Pro	missense_variant	5/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.662T>C	p.Leu221Pro	missense_variant	5/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.662T>C	p.Leu221Pro	missense_variant	5/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.116T>C	p.Leu39Pro	missense_variant	5/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 28, 2020	The ENG c.662T>C; p.Leu221Pro variant is reported in multiple unrelated individuals and families with HHT (Gedge 2007, Kuehl 2005, Pece-Barbara 1999, Nishida 2012, Schulte 2005), and is classified as pathogenic in the ClinVar database (Variation ID: 435060). Experimental studies demonstrated that the variant causes reduced endoglin expression (Pece-Barbara 1999). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 221 is not highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES 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. Kuehl HK et al. Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations. Hum Mutat. 2005 Mar;25(3):320. 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. 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. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	The NM_001114753.3: c.662T>C variant in ENG is a missense variant predicted to cause substitution of leucine by proline at amino acid 221 (p.Leu221Pro). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID: 10545596, 15880681, 17384219, 18498373, 20414677, 22991266, 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 computational predictor REVEL gives a score of 0.478, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, protein expression assays in cell lines showed the variant causes reduced endoglin expression (PS3_Supporting; PMID: 10545596). In summary, this variant meets the criteria to be classified as likely 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: PS4, PP4_Moderate, PS3_Supporting, PM2_Supporting (specification version 1.0.0; 1/4/2024). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 15, 2017	- -

ENG-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 22, 2023

Variant summary: ENG c.662T>C (p.Leu221Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 214184 control chromosomes (gnomAD). c.662T>C has been reported in the literature in individuals affected with Hereditary Hemorrhagic Telangiectasia (examples: Nishida_2012, and Pece-Barbara_1999). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that this variant results in reduced expression of fully processed normal endoglin (Pece-Barbara_1999). The following publications have been ascertained in the context of this evaluation (PMID: 22991266, 10545596). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2019

Published functional studies demonstrate L221P has a damaging effect by leading to protein misfolding and minimal protein expression at the cell surface (Pece-Barbara et al., 1999); Reported in ClinVar as pathogenic but additional evidence is not available (ClinVar Variant ID# 435060; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32300199, 11440987, 18498373, 21158752, 22991266, 17384219, 15880681, 10545596, 15712270, 16690726) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2019

The p.L221P variant (also known as c.662T>C), located in coding exon 5 of the ENG gene, results from a T to C substitution at nucleotide position 662. The leucine at codon 221 is replaced by proline, an amino acid with similar properties. This variant has been reported in multiple individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) (Schulte C et al. Hum Mutat. 2005;25(6):55; Kuehl HK et al. Hum Mutat 2005;25(3):320; Gedge F et al. J Mol Diagn. 2007;9(2):258-65; Brakensiek K et al. Clin Genet. 2008;74(2):171-7). In addition, one study found this variant leads to misfolding of the protein and significant reductions in overall expression on the cell surface in activated monocytes from an individual with a clinical diagnosis of HHT as well as in transfected COS-1 cells (Pece-Barbara N et al. Hum Mol Genet. 1999;8(12):2171-81).This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 07, 2019

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change reduced expression of endonglin (PMID: 10545596). This variant has been reported in several individuals and families affected with hereditary hemorrhagic telangiectasia (PMID: 10545596, 22991266, 15880681, 15712270, 11440987, 21158752, 16690726, 18498373). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 221 of the ENG protein (p.Leu221Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.0	M;.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	D;.;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.97
MutPred		0.86		Gain of disorder (P = 0.009);.;Gain of disorder (P = 0.009);
MVP		0.95
MPC		1.0
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.93

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: rs1554810378; hg19: chr9-130588001;