rs1554809363

Variant names:

• chr9-127818825-A-C
• rs1554809363
• NM_001114753.3:c.1319T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP4_Moderate PM2_Supporting PS4_Moderate PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1319T>G variant in ENG is a missense variant predicted to cause substitution of valine by glycine at amino acid 440 (p.Val440Gly). This variant has been reported in more than 2 probands with a phenotype consistent with HHT (PS4_Moderate; 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 Hereditary Hemorrhagic Telangiectasia in 5 affected meioses from 1 family (PP1_Strong; Internal lab contributors). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.385, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. 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: PP1_Strong, PS4_Moderate, PP4_Moderate, PM2_Supporting (specifications version 1.1.0; 11/12/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA374977914/MONDO:0008535/136

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 4.39

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]

ENSG00000225032 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1319T>G	p.Val440Gly	missense_variant	Exon 11 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1319T>G	p.Val440Gly	missense_variant	Exon 11 of 14		NP_000109.1
ENG	NM_001278138.2	c.773T>G	p.Val258Gly	missense_variant	Exon 11 of 15		NP_001265067.1
LOC102723566	NR_136302.1	n.1568+114A>C		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1319T>G	p.Val440Gly	missense_variant	Exon 11 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1 Uncertain:1

Nov 12, 2024

ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001114753.3: c.1319T>G variant in ENG is a missense variant predicted to cause substitution of valine by glycine at amino acid 440 (p.Val440Gly). This variant has been reported in more than 2 probands with a phenotype consistent with HHT (PS4_Moderate; 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 Hereditary Hemorrhagic Telangiectasia in 5 affected meioses from 1 family (PP1_Strong; Internal lab contributors). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.385, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. 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: PP1_Strong, PS4_Moderate, PP4_Moderate, PM2_Supporting (specifications version 1.1.0; 11/12/2024). -

Mar 12, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ENG c.1319T>G; p.Val440Gly variant, to our knowledge, is not reported in the medical literature but is reported in the ClinVar database (Variation ID: 528065). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 440 is a moderately conserved residue in the zona pellucida domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, a different variant at this codon (p.Val440Met) is reported in the HHT variant database (see link). However, due to limited information, the clinical significance of the p.Val440Gly variant is uncertain at this time. REFERENCES ENG HHT database link: https://arup.utah.edu/database/ENG/ENG_display.php -

not provided Uncertain:2

Dec 07, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_supporting -

Jun 05, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; 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 -

Cardiovascular phenotype Pathogenic:1

May 22, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V440G variant (also known as c.1319T>G), located in coding exon 11 of the ENG gene, results from a T to G substitution at nucleotide position 1319. The valine at codon 440 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with hereditary hemorrhagic telangiectasia (HHT) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is 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

Aug 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 528065). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val440 amino acid residue in ENG. Other variant(s) that disrupt this residue have been observed in individuals with ENG-related conditions (PMID: 34872578; Invitae), which suggests that this may be a clinically significant amino acid residue. 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. This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 440 of the ENG protein (p.Val440Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;T;.
Eigen	Benign	0.082
Eigen_PC	Benign	-0.035
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.60	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.4	L;.;L
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	N;.;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.49
MutPred		0.79		Loss of sheet (P = 0.0181);.;Loss of sheet (P = 0.0181);
MVP		0.84
MPC		0.92
ClinPred		0.87	D
GERP RS		4.5
Varity_R		0.83
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1554809363; hg19: chr9-130581104;