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NM_001114753.3(ENG):c.1465C>T (p.Gln489Ter) AND Telangiectasia, hereditary hemorrhagic, type 1

Germline classification:
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:
RCV002225104.4

Allele description [Variation Report for NM_001114753.3(ENG):c.1465C>T (p.Gln489Ter)]

NM_001114753.3(ENG):c.1465C>T (p.Gln489Ter)

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.1465C>T (p.Gln489Ter)
HGVS:
  • NC_000009.12:g.127818341G>A
  • NG_009551.1:g.41428C>T
  • NM_000118.4:c.1465C>T
  • NM_001114753.3:c.1465C>TMANE SELECT
  • NM_001278138.2:c.919C>T
  • NP_000109.1:p.Gln489Ter
  • NP_000109.1:p.Gln489Ter
  • NP_001108225.1:p.Gln489Ter
  • NP_001108225.1:p.Gln489Ter
  • NP_001265067.1:p.Gln307Ter
  • LRG_589t1:c.1465C>T
  • LRG_589t2:c.1465C>T
  • LRG_589:g.41428C>T
  • LRG_589p1:p.Gln489Ter
  • LRG_589p2:p.Gln489Ter
  • NC_000009.11:g.130580620G>A
  • NM_000118.2:c.1465C>T
  • NM_000118.3:c.1465C>T
  • NM_001114753.1:c.1465C>T
  • NM_001114753.2:c.1465C>T
  • NM_001114753.2:c.1465C>T
  • NR_136302.1:n.1408G>A
Protein change:
Q307*
Links:
dbSNP: rs1057521648
NCBI 1000 Genomes Browser:
rs1057521648
Molecular consequence:
  • NR_136302.1:n.1408G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_000118.4:c.1465C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001114753.3:c.1465C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001278138.2:c.919C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Telangiectasia, hereditary hemorrhagic, 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
SCV002503791Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 30, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002767224Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 6, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Update on molecular diagnosis of hereditary hemorrhagic telangiectasia.

Richards-Yutz J, Grant K, Chao EC, Walther SE, Ganguly A.

Hum Genet. 2010 Jul;128(1):61-77. doi: 10.1007/s00439-010-0825-4. Epub 2010 Apr 23.

PubMed [citation]
PMID:
20414677

A brain abscess following dental extractions in a patient with hereditary hemorrhagic telangiectasia.

Corre P, Perret C, Isidor B, Khonsari RH.

Br J Oral Maxillofac Surg. 2011 Jul;49(5):e9-11. doi: 10.1016/j.bjoms.2010.07.014. Epub 2010 Aug 16.

PubMed [citation]
PMID:
20719417
See all PubMed Citations (4)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV002503791.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature termination codon at position 489 in exon 12 (of 15) of ENG (p.(Gln489*)). This is predicted to result in an absent or disrupted protein product through nonsense mediated decay. Loss of function is a well established disease mechanism for this gene (PVS1). The variant is absent in a large population cohort (PM2, rs1057521648, gnomAD v2.1.1 and v3). The variant has been reported in two unrelated individuals with a clinical diagnosis of hereditary haemorrhagic telangiectasia (PS4_Moderate, PMID: 20414677, 20719417) and is reported to segregate with disease in an affected family (Invitae, ClinVar). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. The following criteria are met: PVS1, PM2, PS4_Moderate.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767224.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Hereditary Hemorrhagic Telangiectasia type 1 (MIM#187300). Loss-of-function variants have been reported, while missense variants have been demonstrated to have both loss of function and dominant negative effects on protein activity (PMID: 25312062). (I). 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported multiple times as pathogenic, and have been observed in many individuals with hereditary hemorrhagic telangiectasia (HHT) (DECIPHER, PMID: 20414677). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and has been observed in several individuals with HHT, or epistaxis and telangiectasia (ClinVar, LOVD, PMID: 20414677, PMID: 20719417). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Jun 23, 2024