NM_000020.3(ACVRL1):c.1445C>A (p.Ala482Glu) AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 29, 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:: RCV003508996.2

Allele description [Variation Report for NM_000020.3(ACVRL1):c.1445C>A (p.Ala482Glu)]

NM_000020.3(ACVRL1):c.1445C>A (p.Ala482Glu)

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.1445C>A (p.Ala482Glu)

HGVS:

NC_000012.12:g.51920826C>A
NG_009549.1:g.18409C>A
NM_000020.3:c.1445C>AMANE SELECT
NM_001077401.2:c.1445C>A
NM_001406487.1:c.1445C>A
NM_001406490.1:c.1289C>A
NM_001406491.1:c.1133C>A
NM_001406492.1:c.1133C>A
NM_001406494.1:c.935C>A
NM_001406495.1:c.881C>A
NP_000011.2:p.Ala482Glu
NP_000011.2:p.Ala482Glu
NP_001070869.1:p.Ala482Glu
NP_001393416.1:p.Ala482Glu
NP_001393419.1:p.Ala430Glu
NP_001393420.1:p.Ala378Glu
NP_001393421.1:p.Ala378Glu
NP_001393423.1:p.Ala312Glu
NP_001393424.1:p.Ala294Glu
LRG_543t1:c.1445C>A
LRG_543:g.18409C>A
LRG_543p1:p.Ala482Glu
NC_000012.11:g.52314610C>A
NM_000020.2:c.1445C>A

Protein change:

A294E

Molecular consequence:

NM_000020.3:c.1445C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001077401.2:c.1445C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406487.1:c.1445C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406490.1:c.1289C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406491.1:c.1133C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406492.1:c.1133C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406494.1:c.935C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406495.1:c.881C>A - 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
SCV004294167	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 29, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17786384, 21158752, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004294167

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 29, 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

Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies.

Olivieri C, Pagella F, Semino L, Lanzarini L, Valacca C, Pilotto A, Corno S, Scappaticci S, Manfredi G, Buscarini E, Danesino C.

J Hum Genet. 2007;52(10):820-829. doi: 10.1007/s10038-007-0187-5. Epub 2007 Sep 5.

PubMed [citation]

PMID:: 17786384

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294167.1

#	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 alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 482 of the ACVRL1 protein (p.Ala482Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 17786384, 21158752; Invitae). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 29, 2024

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