NM_001114753.3(ENG):c.1844C>T (p.Ser615Leu) AND Telangiectasia, hereditary hemorrhagic, type 1

Germline classification:: Likely benign (6 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:: RCV000230696.15

Allele description [Variation Report for NM_001114753.3(ENG):c.1844C>T (p.Ser615Leu)]

NM_001114753.3(ENG):c.1844C>T (p.Ser615Leu)

Gene:

ENG:endoglin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.11

Genomic location:

Preferred name:

NM_001114753.3(ENG):c.1844C>T (p.Ser615Leu)

Other names:

NM_000118.3(ENG):c.1844C>T(p.Ser615Leu); NM_001114753.2(ENG):c.1844C>T(p.Ser615Leu); NM_001278138.1(ENG):c.1298C>T(p.Ser433Leu); NM_001114753.3(ENG):c.1844C>T

HGVS:

NC_000009.12:g.127815951G>A
NG_009551.1:g.43818C>T
NG_023245.1:g.18077G>A
NM_000118.4:c.1844C>T
NM_001114753.3:c.1844C>TMANE SELECT
NM_001278138.2:c.1298C>T
NP_000109.1:p.Ser615Leu
NP_000109.1:p.Ser615Leu
NP_001108225.1:p.Ser615Leu
NP_001108225.1:p.Ser615Leu
NP_001265067.1:p.Ser433Leu
LRG_589t1:c.1844C>T
LRG_589t2:c.1844C>T
LRG_589:g.43818C>T
LRG_589p1:p.Ser615Leu
LRG_589p2:p.Ser615Leu
NC_000009.11:g.130578230G>A
NM_000118.2:c.1844C>T
NM_000118.3:c.1844C>T
NM_001114753.1:c.1844C>T
NM_001114753.2:c.1844C>T
P17813:p.Ser615Leu

Protein change:

S433L

Links:

UniProtKB: P17813#VAR_026783; dbSNP: rs148002300

NCBI 1000 Genomes Browser:

rs148002300

Molecular consequence:

NM_000118.4:c.1844C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001114753.3:c.1844C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001278138.2:c.1298C>T - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000477309	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Likely benign (Jun 14, 2016)	germline	clinical testing	ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000803471	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (May 31, 2018)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 15712270, 25741868
SCV000883788	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Benign (Jun 28, 2023)	germline	clinical testing	Citation Link,
SCV001137908	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001439440	NIHR Bioresource Rare Diseases, University of Cambridge	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jan 1, 2018)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 32573726, 25741868
SCV004805880	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen HHT ACMG Specifications ENG V1.1.0)	Likely Benign (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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations.

Kuehl HK, Caselitz M, Hasenkamp S, Wagner S, El-Harith el-HA, Manns MP, Stuhrmann M.

Hum Mutat. 2005 Mar;25(3):320.

PubMed [citation]

PMID:: 15712270

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 Illumina Laboratory Services, Illumina, SCV000477309.2

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

#	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 SIB Swiss Institute of Bioinformatics, SCV000803471.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

This variant is interpreted as a Likely Benign, for Telangiectasia, hereditary hemorrhagic, type 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder (http://exac.broadinstitute.org/variant/9-130578230-G-A). BS2-Supporting => BS2 downgraded in strength to supporting. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:15712270).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883788.2

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

#	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 Mendelics, SCV001137908.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From NIHR Bioresource Rare Diseases, University of Cambridge, SCV001439440.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)

Description

BS1 +BP2+BP6

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen, SCV004805880.1

#	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.1844C>T variant in ENG is a missense variant predicted to cause substitution of serine by leucine at amino acid 615 (p.Ser615Leu). The filtering allele frequency (the lower threshold of the 95% CI of 285/115780) of the c.1844C>T variant in ENG is 0.002284 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 1 patient with an alternate molecular basis for disease (patient also carries a likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID: 15712270). The computational predictor REVEL gives a score of 0.188, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062, 22022569). In summary, this variant meets the criteria to be classified as likely benign 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: BS1, BP5, BS3_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: Oct 20, 2024

ClinVar

Relating variation to medicine