NM_000020.3(ACVRL1):c.866T>C (p.Leu289Pro) AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 6, 2023
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:: RCV003099999.2

Allele description [Variation Report for NM_000020.3(ACVRL1):c.866T>C (p.Leu289Pro)]

NM_000020.3(ACVRL1):c.866T>C (p.Leu289Pro)

Gene:

ACVRL1:activin A receptor like type 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.13

Genomic location:

Preferred name:

NM_000020.3(ACVRL1):c.866T>C (p.Leu289Pro)

HGVS:

NC_000012.12:g.51915318T>C
NG_009549.1:g.12901T>C
NM_000020.3:c.866T>CMANE SELECT
NM_001077401.2:c.866T>C
NM_001406487.1:c.866T>C
NM_001406488.1:c.866T>C
NM_001406489.1:c.866T>C
NM_001406490.1:c.554T>C
NM_001406491.1:c.554T>C
NM_001406492.1:c.554T>C
NM_001406493.1:c.554T>C
NM_001406494.1:c.554T>C
NM_001406495.1:c.302T>C
NP_000011.2:p.Leu289Pro
NP_000011.2:p.Leu289Pro
NP_001070869.1:p.Leu289Pro
NP_001393416.1:p.Leu289Pro
NP_001393417.1:p.Leu289Pro
NP_001393418.1:p.Leu289Pro
NP_001393419.1:p.Leu185Pro
NP_001393420.1:p.Leu185Pro
NP_001393421.1:p.Leu185Pro
NP_001393422.1:p.Leu185Pro
NP_001393423.1:p.Leu185Pro
NP_001393424.1:p.Leu101Pro
LRG_543t1:c.866T>C
LRG_543:g.12901T>C
LRG_543p1:p.Leu289Pro
NC_000012.11:g.52309102T>C
NM_000020.2:c.866T>C

Protein change:

L101P

Molecular consequence:

NM_000020.3:c.866T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001077401.2:c.866T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406487.1:c.866T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406488.1:c.866T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406489.1:c.866T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406490.1:c.554T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406491.1:c.554T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406492.1:c.554T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406493.1:c.554T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406494.1:c.554T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406495.1:c.302T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Telangiectasia, hereditary hemorrhagic, type 2 (HHT2)
Synonyms:: Telangiectasia, hereditary hemorrhagic, type II; Osler Weber Rendu syndrome type 2
Identifiers:: MONDO: MONDO:0010880; MedGen: C1838163; Orphanet: 774; OMIM: 600376

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003441133	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16752392, 32300199, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003441133

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 6, 2023)

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

Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype.

Bossler AD, Richards J, George C, Godmilow L, Ganguly A.

Hum Mutat. 2006 Jul;27(7):667-75.

PubMed [citation]

PMID:: 16752392

Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2).

McDonald J, Bayrak-Toydemir P, DeMille D, Wooderchak-Donahue W, Whitehead K.

Genet Med. 2020 Jul;22(7):1201-1205. doi: 10.1038/s41436-020-0775-8. Epub 2020 Apr 17.

PubMed [citation]

PMID:: 32300199

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003441133.2

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

Description

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function. ClinVar contains an entry for this variant (Variation ID: 1764244). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 16752392, 32300199). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 289 of the ACVRL1 protein (p.Leu289Pro).

#	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 1, 2024

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