NM_001114753.3(ENG):c.1311+2T>C AND Hereditary hemorrhagic telangiectasia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 30, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003062234.5

Allele description [Variation Report for NM_001114753.3(ENG):c.1311+2T>C]

NM_001114753.3(ENG):c.1311+2T>C

Genes:

ENG:endoglin [Gene - OMIM - HGNC]
LOC102723566:uncharacterized LOC102723566 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.11

Genomic location:

Preferred name:

NM_001114753.3(ENG):c.1311+2T>C

HGVS:

NC_000009.12:g.127819620A>G
NG_009551.1:g.40149T>C
NM_000118.4:c.1311+2T>C
NM_001114753.3:c.1311+2T>CMANE SELECT
NM_001278138.2:c.765+2T>C
LRG_589:g.40149T>C
NC_000009.11:g.130581899A>G
NM_001114753.2:c.1311+2T>C

Molecular consequence:

NM_000118.4:c.1311+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001114753.3:c.1311+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001278138.2:c.765+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hereditary hemorrhagic telangiectasia (HHT)
Synonyms:: ORW DISEASE; Osler Weber Rendu syndrome; OSLER-RENDU-WEBER DISEASE; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0019180; MedGen: C0039445; OMIM: PS187300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003441486	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 27, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16752392, 21158752, 16199547, 15879500, 28492532
SCV004812436	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 30, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9554745, 10625079, 15517393, 16752392, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003441486

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 27, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004812436

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 30, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis.

McDonald J, Damjanovich K, Millson A, Wooderchak W, Chibuk JM, Stevenson DA, Gedge F, Bayrak-Toydemir P.

Clin Genet. 2011 Apr;79(4):335-44. doi: 10.1111/j.1399-0004.2010.01596.x. Epub 2010 Dec 16.

PubMed [citation]

PMID:: 21158752

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003441486.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 16752392, 21158752). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 of the ENG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Genetics, Royal Melbourne Hospital, SCV004812436.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change in ENG occurs within the canonical splice donor site (+ 2) of intron 10. It is predicted to cause skipping of biologically relevant-exon 10, resulting in an in-frame deletion (removes amino acids 425-437) that is expected to escape nonsense-mediated decay and remove <10% of the protein. The region of the Zona Pellucida domain removed is expected to be critical to protein function because multiple pathogenic variants altering this splice site have been reported (c.1311+2T>A, c.1311+2T>G, c.1311G>C, c.1311G>A; ARUP ENG database; PMID: 9554745, 10625079, 15517393). This variant is absent from the population database gnomAD v2.1 and v3.1. It has been reported in at least two probands with a clinical diagnosis of hereditary haemorrhagic telangiectasia (PMID: 16752392; internal laboratory data). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PS4_Moderate, PM2_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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