rs863223539

Variant names:

• chr9-127817175-A-T
• rs863223539
• NM_001114753.3:c.1715T>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.1715T>A​(p.Leu572*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 33)
• Consequence: ENG NM_001114753.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.34

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 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 9-127817175-A-T is Pathogenic according to our data. Variant chr9-127817175-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 213213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1715T>A	p.Leu572*	stop_gained	Exon 13 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1715T>A	p.Leu572*	stop_gained	Exon 13 of 14		NP_000109.1
ENG	NM_001278138.2	c.1169T>A	p.Leu390*	stop_gained	Exon 13 of 15		NP_001265067.1
LOC102723566	NR_136302.1	n.1110A>T		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1715T>A	p.Leu572*	stop_gained	Exon 13 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.1715T>A	p.Leu572*	stop_gained	Exon 13 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.1169T>A	p.Leu390*	stop_gained	Exon 13 of 15	2		ENSP00000479015.1
ENSG00000225032	ENST00000439298.5	n.1110A>T		non_coding_transcript_exon_variant	Exon 1 of 6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 23, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PS3_supporting, PS4_moderate, PVS1 -

Mar 20, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in two individuals from one family with pulmonary and cerebral arteriovenous malformations, and also identified in a patient with cerebral and pulmonary arteriovenous malformations, stroke, and epistaxis referred for genetic testing at GeneDx (PMID: 11440987); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as p.(L572*) results in low levels of truncated endoglin protein and causes impaired endoglin secretion (PMID: 11440987); Nonsense variant predicted to result in protein truncation, as the last 54amino acid(s) are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 25525159, 15907823, 11440987) -

ENG-related disorder Pathogenic:1

Aug 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ENG c.1715T>A variant is predicted to result in premature protein termination (p.Leu572*). This variant has been reported in an individual with hereditary hemorrhagic telangiectasia (referred to as T1715A in Paquet et al. 2001. PubMed ID: 11440987). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in ENG are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Apr 05, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L572* pathogenic mutation (also known as c.1715T>A), located in coding exon 13 of the ENG gene, results from a T to A substitution at nucleotide position 1715. This changes the amino acid from a leucine to a stop codon within coding exon 13. This mutation was described in a family with both pulmonary and cerebral arteriovenous malformations. In addition, in vitro studies suggested impaired processing and undetectable level of truncated protein (Paquet ME et al. Hum. Mol. Genet., 2001 Jun;10:1347-57). 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

Aug 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu572*) in the ENG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the ENG protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 11440987; Invitae). This variant is also known as delta571. ClinVar contains an entry for this variant (Variation ID: 213213). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ENG function (PMID: 11440987). This variant disrupts the C-terminus of the ENG protein. Other variant(s) that disrupt this region (p.Pro577Argfs*42, p.Ile602Serfs*38) have been observed in individuals with ENG-related conditions (PMID: 21158752, 23919827). This suggests that this may be a clinically significant region of the protein. 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	0.35
CADD	Pathogenic	36
DANN	Uncertain	0.98
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.45	N
Vest4		0.74
GERP RS		3.6

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: rs863223539; hg19: chr9-130579454;