NM_001114753.3(ENG):c.1019C>T (p.Pro340Leu) AND Hereditary hemorrhagic telangiectasia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 24, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002533781.1

Allele description [Variation Report for NM_001114753.3(ENG):c.1019C>T (p.Pro340Leu)]

NM_001114753.3(ENG):c.1019C>T (p.Pro340Leu)

Gene:

ENG:endoglin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.11

Genomic location:

Preferred name:

NM_001114753.3(ENG):c.1019C>T (p.Pro340Leu)

HGVS:

NC_000009.12:g.127824419G>A
NG_009551.1:g.35350C>T
NM_000118.4:c.1019C>T
NM_001114753.3:c.1019C>TMANE SELECT
NM_001278138.2:c.473C>T
NM_001406715.1:c.1019C>T
NP_000109.1:p.Pro340Leu
NP_000109.1:p.Pro340Leu
NP_001108225.1:p.Pro340Leu
NP_001108225.1:p.Pro340Leu
NP_001265067.1:p.Pro158Leu
NP_001393644.1:p.Pro340Leu
LRG_589t1:c.1019C>T
LRG_589t2:c.1019C>T
LRG_589:g.35350C>T
LRG_589p1:p.Pro340Leu
LRG_589p2:p.Pro340Leu
NC_000009.11:g.130586698G>A
NM_000118.3:c.1019C>T
NM_001114753.2:c.1019C>T

Protein change:

P158L

Links:

dbSNP: rs772135786

NCBI 1000 Genomes Browser:

rs772135786

Molecular consequence:

NM_000118.4:c.1019C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001114753.3:c.1019C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001278138.2:c.473C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406715.1:c.1019C>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002952672	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 24, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21158752, 25312062, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002952672

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 24, 2022)

germline

clinical testing

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

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

Citations

PubMed

Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis.

McDonald J, Damjanovich K, Millson A, Wooderchak W, Chibuk JM, Stevenson DA, Gedge F, Bayrak-Toydemir P.

Clin Genet. 2011 Apr;79(4):335-44. doi: 10.1111/j.1399-0004.2010.01596.x. Epub 2010 Dec 16.

PubMed [citation]

PMID:: 21158752

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

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002952672.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 340 of the ENG protein (p.Pro340Leu). This variant is present in population databases (rs772135786, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia, however in one of these individuals a pathogenic variant was also identified in the ACVRL1 gene (PMID: 21158752). ClinVar contains an entry for this variant (Variation ID: 618084). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect ENG function (PMID: 25312062). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

#	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: May 19, 2024

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