NM_001114753.3(ENG):c.662T>C (p.Leu221Pro) AND Telangiectasia, hereditary hemorrhagic, type 1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Mar 15, 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:: RCV000500817.14

Allele description [Variation Report for NM_001114753.3(ENG):c.662T>C (p.Leu221Pro)]

NM_001114753.3(ENG):c.662T>C (p.Leu221Pro)

Gene:

ENG:endoglin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.11

Genomic location:

Preferred name:

NM_001114753.3(ENG):c.662T>C (p.Leu221Pro)

Other names:

NM_001114753.3(ENG):c.662T>C; p.Leu221Pro

HGVS:

NC_000009.12:g.127825722A>G
NG_009551.1:g.34047T>C
NM_000118.4:c.662T>C
NM_001114753.3:c.662T>CMANE SELECT
NM_001278138.2:c.116T>C
NM_001406715.1:c.662T>C
NP_000109.1:p.Leu221Pro
NP_000109.1:p.Leu221Pro
NP_001108225.1:p.Leu221Pro
NP_001108225.1:p.Leu221Pro
NP_001265067.1:p.Leu39Pro
NP_001393644.1:p.Leu221Pro
LRG_589t1:c.662T>C
LRG_589t2:c.662T>C
LRG_589:g.34047T>C
LRG_589p1:p.Leu221Pro
LRG_589p2:p.Leu221Pro
NC_000009.11:g.130588001A>G
NM_000118.2:c.662T>C
NM_000118.3:c.662T>C
NM_001114753.1:c.662T>C
NM_001114753.2:c.662T>C

Protein change:

L221P

Links:

dbSNP: rs1554810378

NCBI 1000 Genomes Browser:

rs1554810378

Molecular consequence:

NM_000118.4:c.662T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001114753.3:c.662T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001278138.2:c.116T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406715.1:c.662T>C - 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
SCV000594549	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 15, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001474417	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Apr 28, 2020)	germline	clinical testing	Citation Link,
SCV004805873	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen HHT ACMG Specifications ENG V1.1.0)	Likely Pathogenic (Mar 15, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000594549

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 15, 2017)

germline

clinical testing

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

SCV001474417

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Apr 28, 2020)

germline

clinical testing

Citation Link,

SCV004805873

ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen HHT ACMG Specifications ENG V1.1.0)

Likely Pathogenic
(Mar 15, 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	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, curation

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 Genetic Services Laboratory, University of Chicago, SCV000594549.1

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001474417.1

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

Description

The ENG c.662T>C; p.Leu221Pro variant is reported in multiple unrelated individuals and families with HHT (Gedge 2007, Kuehl 2005, Pece-Barbara 1999, Nishida 2012, Schulte 2005), and is classified as pathogenic in the ClinVar database (Variation ID: 435060). Experimental studies demonstrated that the variant causes reduced endoglin expression (Pece-Barbara 1999). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 221 is not highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. Kuehl HK et al. Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations. Hum Mutat. 2005 Mar;25(3):320. Pece-Barbara N et al. Expression analysis of four endoglin missense mutations suggests that haploinsufficiency is the predominant mechanism for hereditary hemorrhagic telangiectasia type 1. Hum Mol Genet. 1999 Nov;8(12):2171-81. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595.

#	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 ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen, SCV004805873.1

#	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.662T>C variant in ENG is a missense variant predicted to cause substitution of leucine by proline at amino acid 221 (p.Leu221Pro). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID: 10545596, 15880681, 17384219, 18498373, 20414677, 22991266, 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 computational predictor REVEL gives a score of 0.478, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, protein expression assays in cell lines showed the variant causes reduced endoglin expression (PS3_Supporting; PMID: 10545596). In summary, this variant meets the criteria to be classified as likely 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: PS4, PP4_Moderate, PS3_Supporting, PM2_Supporting (specification version 1.0.0; 1/4/2024).

#	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: Apr 6, 2024

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