NM_000020.3(ACVRL1):c.632G>A (p.Gly211Asp) AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Apr 12, 2019
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:: RCV001001392.9

Allele description [Variation Report for NM_000020.3(ACVRL1):c.632G>A (p.Gly211Asp)]

NM_000020.3(ACVRL1):c.632G>A (p.Gly211Asp)

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.632G>A (p.Gly211Asp)

HGVS:

NC_000012.12:g.51914445G>A
NG_009549.1:g.12028G>A
NM_000020.3:c.632G>AMANE SELECT
NM_001077401.2:c.632G>A
NP_000011.2:p.Gly211Asp
NP_000011.2:p.Gly211Asp
NP_001070869.1:p.Gly211Asp
LRG_543t1:c.632G>A
LRG_543:g.12028G>A
LRG_543p1:p.Gly211Asp
NC_000012.11:g.52308229G>A
NM_000020.2:c.632G>A
P37023:p.Gly211Asp

Protein change:

G211D; GLY211ASP

Links:

UniProtKB: P37023#VAR_026788; OMIM: 601284.0011; dbSNP: rs28936687

NCBI 1000 Genomes Browser:

rs28936687

Molecular consequence:

NM_000020.3:c.632G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001077401.2:c.632G>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
SCV001158598	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Apr 12, 2019)	germline	clinical testing	Citation Link,
SCV001439467	NIHR Bioresource Rare Diseases, University of Cambridge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2018)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 32573726, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001158598

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Apr 12, 2019)

germline

clinical testing

Citation Link,

SCV001439467

NIHR Bioresource Rare Diseases, University of Cambridge

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 1, 2018)

unknown

research

PubMed (2)
[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
not provided	unknown	yes	5	not provided	not provided	not provided	not provided	research

Citations

PubMed

Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia.

Shovlin CL, Simeoni I, Downes K, Frazer ZC, Megy K, Bernabeu-Herrero ME, Shurr A, Brimley J, Patel D, Kell L, Stephens J, Turbin IG, Aldred MA, Penkett CJ, Ouwehand WH, Jovine L, Turro E.

Blood. 2020 Oct 22;136(17):1907-1918. doi: 10.1182/blood.2019004560.

PubMed [citation]

PMID:: 32573726
PMCID:: PMC7717479

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001158598.1

#	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.632G>A; p.Gly211Asp variant (rs28936687) is reported in the medical literature in an individual with HHT and pulmonary hypertension (Harrison 2003). ARUP has also detected this variant in an individual with a clinical diagnosis of HHT and family history. Additionally, other variants in this codon, p.Gly211Ser and p.Gly211Cys, have been described in individuals with a diagnosis of HHT or pulmonary hypertension (Heimdal 2016, Yang 2018). The c.632G>A; p.Gly211Asp variant is reported in the ClinVar database (Variation ID: 8253) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The amino acid at this position is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic. References: Harrison RE et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003 Dec;40(12):865-71. Heimdal K et al. Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1. Clin Genet. 2016 Feb;89(2):182-6. Yang H et al. Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients. Respir Res. 2018 May 9;19(1):87.

#	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 NIHR Bioresource Rare Diseases, University of Cambridge, SCV001439467.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	research	PubMed (2)

Description

PS3+PM2+PP4+PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Mar 4, 2023

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