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

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Apr 12, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001001392.2

Allele description [Variation Report for NM_000020.2(ACVRL1):c.632G>A (p.Gly211Asp)]

NM_000020.2(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_000020.2(ACVRL1):c.632G>A (p.Gly211Asp)
HGVS:
  • NC_000012.12:g.51914445G>A
  • NG_009549.1:g.12028G>A
  • NM_000020.2:c.632G>A
  • NM_001077401.2:c.632G>A
  • 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
  • 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_000020.2: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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001158598ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Apr 12, 2019)
germlineclinical testing

Citation Link,

SCV001439467NIHR Bioresource Rare Diseases, University of Cambridgecriteria provided, single submitter
Likely pathogenic
(Jan 1, 2018)
unknownresearch

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes5not providednot providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided5not providednot providedresearch PubMed (2)

Description

PS3+PM2+PP4+PP5

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided5not providednot providednot provided

Last Updated: Apr 12, 2021

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