NM_000020.3(ACVRL1):c.1415G>A (p.Trp472Ter) AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 14, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001924863.4

Allele description [Variation Report for NM_000020.3(ACVRL1):c.1415G>A (p.Trp472Ter)]

NM_000020.3(ACVRL1):c.1415G>A (p.Trp472Ter)

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.1415G>A (p.Trp472Ter)

Other names:

p.Trp472*

HGVS:

NC_000012.12:g.51920796G>A
NG_009549.1:g.18379G>A
NM_000020.2:c.1415G>A
NM_000020.3:c.1415G>AMANE SELECT
NM_001077401.2:c.1415G>A
NP_000011.2:p.Trp472Ter
NP_001070869.1:p.Trp472Ter
LRG_543:g.18379G>A
NC_000012.11:g.52314580G>A

Protein change:

W472*

Links:

dbSNP: rs1555154144

NCBI 1000 Genomes Browser:

rs1555154144

Molecular consequence:

NM_000020.3:c.1415G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001077401.2:c.1415G>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV002157418	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 14, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 15024723, 15065824, 15517393, 15712271, 16429404, 16540754, 18673552, 21158752, 23722869, 28492532
SCV004563522	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 2, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002157418

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 14, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV004563522

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Pathogenic
(Nov 2, 2023)

germline

clinical testing

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

Citations

PubMed

Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.

Lesca G, Plauchu H, Coulet F, Lefebvre S, Plessis G, Odent S, Rivière S, Leheup B, Goizet C, Carette MF, Cordier JF, Pinson S, Soubrier F, Calender A, Giraud S; French Rendu-Osler Network..

Hum Mutat. 2004 Apr;23(4):289-99.

PubMed [citation]

PMID:: 15024723

Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia.

Abdalla SA, Gallione CJ, Barst RJ, Horn EM, Knowles JA, Marchuk DA, Letarte M, Morse JH.

Eur Respir J. 2004 Mar;23(3):373-7.

PubMed [citation]

PMID:: 15065824

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002157418.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change creates a premature translational stop signal (p.Trp472*) in the ACVRL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the ACVRL1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACVRL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1384566). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the ACVRL1 protein in which other variant(s) (p.Arg479*) have been determined to be pathogenic (PMID: 15024723, 15065824, 15517393, 15712271, 16429404, 16540754, 18673552, 21158752, 23722869). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563522.1

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

Description

The ACVRL1 c.1415G>A; p.Trp472Ter variant (rs1555154144) is reported in the literature in an individual with HHT (Baysal 2021). This variant is also reported in ClinVar (Variation ID: 1384566). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the ACVRL1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein. Based on available information, this variant is considered to be pathogenic. References: Baysal M et al. A Novel Variant in the ACVRL1 Gene in a Patient with Cirrhosis and Hereditary Hemorrhagic Telangiectasia. Turk J Haematol. 2021 Aug 25;38(3):241-243. PMID: 33754658.

#	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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