NM_001114753.3(ENG):c.360+1G>A AND Hereditary hemorrhagic telangiectasia type 1

Clinical significance:Pathogenic (Last evaluated: Jul 31, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000274164.7

Allele description [Variation Report for NM_001114753.3(ENG):c.360+1G>A]

NM_001114753.3(ENG):c.360+1G>A

Gene:
ENG:endoglin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9q34.11
Genomic location:
Preferred name:
NM_001114753.3(ENG):c.360+1G>A
HGVS:
  • NC_000009.12:g.127829686C>T
  • NG_009551.1:g.30083G>A
  • NM_000118.3:c.360+1G>A
  • NM_001114753.3:c.360+1G>AMANE SELECT
  • NM_001278138.2:c.-187+1G>A
  • LRG_589t1:c.360+1G>A
  • LRG_589:g.30083G>A
  • NC_000009.11:g.130591965C>T
  • NC_000009.11:g.130591965C>T
  • NM_000118.2:c.360+1G>A
Nucleotide change:
IVS3DS, G-A, +1
Links:
OMIM: 131195.0005; dbSNP: rs886039505
NCBI 1000 Genomes Browser:
rs886039505
Molecular consequence:
  • NM_000118.3:c.360+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001114753.3:c.360+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001278138.2:c.-187+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Hereditary hemorrhagic telangiectasia type 1 (HHT1)
Synonyms:
Osler Weber Rendu syndrome type 1
Identifiers:
MONDO: MONDO:0008535; MedGen: C4551861; Orphanet: 774; OMIM: 187300

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000038431OMIMno assertion criteria providedPathogenic
(Nov 15, 1997)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV001441154NIHR Bioresource Rare Diseases, University of Cambridgecriteria provided, single submitter
Pathogenic
(Jan 1, 2018)
unknownresearch

PubMed (2)
[See all records that cite these PMIDs]

SCV001474418ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Jul 31, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes2not providednot providednot providednot providedresearch
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative.

Pece N, Vera S, Cymerman U, White RI Jr, Wrana JL, Letarte M.

J Clin Invest. 1997 Nov 15;100(10):2568-79.

PubMed [citation]
PMID:
9366572
PMCID:
PMC508458

Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia.

Shovlin CL, Simeoni I, Downes K, Frazer ZC, Megy K, Bernabeu-Herrero ME, Shurr A, Brimley J, Patel D, Kell L, Stephens J, Turbin IG, Aldred MA, Penkett CJ, Ouwehand WH, Jovine L, Turro E.

Blood. 2020 Oct 22;136(17):1907-1918. doi: 10.1182/blood.2019004560.

PubMed [citation]
PMID:
32573726
PMCID:
PMC7717479
See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000038431.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a patient with hereditary hemorrhagic telangiectasia-1 (HHT1; 187300), Pece et al. (1997) detected a splice site mutation of the ENG gene, resulting in in-frame deletion of exon 3 from the transcript and a truncated polypeptide.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From NIHR Bioresource Rare Diseases, University of Cambridge, SCV001441154.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedresearch PubMed (2)

Description

PVS1+PM2+PP4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided2not providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001474418.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ENG c.360+1G>A variant (rs886039505) is reported in the literature in multiple individuals and families with hereditary hemorrhagic telangiectasia (ENG HHT database, Heimdal 2016, Kim 2011, McDonald 2011, Nishida 2012, Pece 1997, Sadick 2009, Schulte 2005). This variant is reported as pathogenic three times in ClinVar (Variation ID: 265370), but is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Functional analysis shows that this variant disrupts the canonical splice donor site in the 5’ end of intron 3 and leads to skipping of exon 3 (Pece 1997). Based on the above information, this variant is considered pathogenic. REFERENCES ENG HHT database: http://arup.utah.edu/database/ENG/ENG_display.php Heimdal K et al. Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1. Clin Genet. 2016 Feb;89(2):182-6. Kim M et al. Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2011; 12: 130. 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; 0(11): 2829–2834. Pece N et al. Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative. J Clin Invest. 1997 Nov 15;100(10):2568-79. Sadick H et al. Mutation analysis of "Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique. BMC Med Genet. 2009; 10: 53. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 25, 2021

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