NM_000020.3(ACVRL1):c.872_873del (p.Arg291fs) AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 10, 2022
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:: RCV000799743.12

Allele description [Variation Report for NM_000020.3(ACVRL1):c.872_873del (p.Arg291fs)]

NM_000020.3(ACVRL1):c.872_873del (p.Arg291fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

12q13.13

Genomic location:

Preferred name:

NM_000020.3(ACVRL1):c.872_873del (p.Arg291fs)

HGVS:

NC_000012.11:g.52309105_52309106delAG
NC_000012.12:g.51915322GA[1]
NG_009549.1:g.12905GA[1]
NM_000020.3:c.872_873delMANE SELECT
NM_001077401.2:c.872_873del
NP_000011.2:p.Arg291fs
NP_001070869.1:p.Arg291fs
LRG_543:g.12905GA[1]
NC_000012.11:g.52309105_52309106del
NC_000012.11:g.52309105_52309106delAG
NC_000012.11:g.52309106GA[1]
NC_000012.11:g.52309108_52309109delGA
NM_000020.2:c.872_873delGA
NM_000020.3:c.872_873delGAMANE SELECT

Protein change:

R291fs

Links:

dbSNP: rs1592224087

NCBI 1000 Genomes Browser:

rs1592224087

Molecular consequence:

NM_000020.3:c.872_873del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001077401.2:c.872_873del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000939419	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 11, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15879500, 28492532
SCV002506173	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Jan 10, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000939419

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 11, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002506173

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Pathogenic
(Jan 10, 2022)

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

Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease.

Abdalla SA, Letarte M.

J Med Genet. 2006 Feb;43(2):97-110. Epub 2005 May 6. Review.

PubMed [citation]

PMID:: 15879500
PMCID:: PMC2603035

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000939419.4

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

Description

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). This variant has not been reported in the literature in individuals with ACVRL1-related disease. This sequence change creates a premature translational stop signal (p.Arg291Thrfs*100) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein product.

#	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, SCV002506173.2

#	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.872_873delGA; p.Arg291ThrfsTer100 variant (rs1592224087), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 645621). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deletion two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be 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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