NM_001114753.3(ENG):c.321_322delinsTT (p.His108Tyr) AND Hereditary hemorrhagic telangiectasia

Clinical significance:Uncertain significance (Last evaluated: Oct 21, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000473361.6

Allele description [Variation Report for NM_001114753.3(ENG):c.321_322delinsTT (p.His108Tyr)]

NM_001114753.3(ENG):c.321_322delinsTT (p.His108Tyr)

Gene:
ENG:endoglin [Gene - OMIM - HGNC]
Variant type:
Indel
Cytogenetic location:
9q34.11
Genomic location:
Preferred name:
NM_001114753.3(ENG):c.321_322delinsTT (p.His108Tyr)
HGVS:
  • NC_000009.12:g.127829725_127829726delinsAA
  • NG_009551.1:g.30043_30044delinsTT
  • NM_000118.3:c.321_322delinsTT
  • NM_001114753.3:c.321_322delinsTTMANE SELECT
  • NM_001278138.1:c.-226_-225delinsTT
  • NP_000109.1:p.His108Tyr
  • NP_001108225.1:p.His108Tyr
  • LRG_589t1:c.321_322delinsTT
  • LRG_589:g.30043_30044delinsTT
  • LRG_589p1:p.His108Tyr
  • NC_000009.11:g.130592004_130592005delinsAA
  • NM_000118.3:c.321_322delGCinsTT
  • NM_001114753.1:c.321_322delinsTT
Protein change:
H108Y
Links:
dbSNP: rs1060501425
NCBI 1000 Genomes Browser:
rs1060501425
Molecular consequence:
  • NM_000118.3:c.321_322delinsTT - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000546134Invitaecriteria provided, single submitter
Uncertain significance
(Oct 21, 2020)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function.

Mallet C, Lamribet K, Giraud S, Dupuis-Girod S, Feige JJ, Bailly S, Tillet E.

Hum Mol Genet. 2015 Feb 15;24(4):1142-54. doi: 10.1093/hmg/ddu531. Epub 2014 Oct 13.

PubMed [citation]
PMID:
25312062

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000546134.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces histidine with tyrosine at codon 108 of the ENG protein (p.His108Tyr). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hereditary hemorrhagic telangiectasia, and a different pathogenic ENG variant was also detected in this individual (PMID: 25312062). It is unknown if these variants are on the same or opposite chromosomes, therefore the clinical significance of the c.321_322delGCinsTT variant is unclear. Experimental studies have shown that this missense change does not affect ENG cellular localization and response to BMP9 (PMID: 25312062). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Jul 7, 2021

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