NM_001114753.3(ENG):c.1586G>A (p.Arg529His) AND Telangiectasia, hereditary hemorrhagic, type 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 11, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000229345.10

Allele description [Variation Report for NM_001114753.3(ENG):c.1586G>A (p.Arg529His)]

NM_001114753.3(ENG):c.1586G>A (p.Arg529His)

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.1586G>A (p.Arg529His)

Other names:

p.R529H:CGC>CAC; NM_001114753.3(ENG):c.1586G>A

HGVS:

NC_000009.12:g.127818220C>T
NG_009551.1:g.41549G>A
NM_000118.4:c.1586G>A
NM_001114753.3:c.1586G>AMANE SELECT
NM_001278138.2:c.1040G>A
NP_000109.1:p.Arg529His
NP_000109.1:p.Arg529His
NP_001108225.1:p.Arg529His
NP_001108225.1:p.Arg529His
NP_001265067.1:p.Arg347His
LRG_589t1:c.1586G>A
LRG_589t2:c.1586G>A
LRG_589:g.41549G>A
LRG_589p1:p.Arg529His
LRG_589p2:p.Arg529His
NC_000009.11:g.130580499C>T
NM_000118.2:c.1586G>A
NM_000118.3:c.1586G>A
NM_001114753.1:c.1586G>A
NM_001114753.2:c.1586G>A
P17813:p.Arg529His
p.(Arg529His)

Protein change:

R347H

Links:

UniProtKB: P17813#VAR_070299; dbSNP: rs863223538

NCBI 1000 Genomes Browser:

rs863223538

Molecular consequence:

NM_000118.4:c.1586G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001114753.3:c.1586G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278138.2:c.1040G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000590887	Center of Genomic medicine, Geneva, University Hospital of Geneva	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 16, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003799021	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 9, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005326488	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen HHT ACMG Specifications ENG V1.1.0)	Pathogenic (Sep 11, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000590887

Center of Genomic medicine, Geneva, University Hospital of Geneva

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 16, 2017)

germline

clinical testing

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

SCV003799021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 9, 2022)

germline

clinical testing

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

SCV005326488

ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen HHT ACMG Specifications ENG V1.1.0)

Pathogenic
(Sep 11, 2024)

germline

curation

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Center of Genomic medicine, Geneva, University Hospital of Geneva, SCV000590887.1

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

#	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

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV003799021.2

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

Description

PS3, PM1, PM2

#	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

From ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen, SCV005326488.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_001114753.3: c.1586G>A variant in ENG is a missense variant predicted to cause substitution of arginine by histidine at amino acid 529 (p.Arg529His). This variant has been reported in more than 10 probands with a phenotype consistent with HHT (PS4; PMID: 22991266, 16752392, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with HHT in more than 20 affected family members from multiple families (PP1_Strong; Internal lab contributors). The overall minor allele frequency in gnomAD v2.1.1 is 0.000004 (1/251282 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.579, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4, PP4_Moderate, PP1_Strong (specifications version 1.1.0; 09/11/2024).

#	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

Last Updated: Jan 13, 2025

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