NM_001077401.2(ACVRL1):c.1232G>A (p.Arg411Gln) AND Telangiectasia, hereditary hemorrhagic, type 2

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 6, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
7 submissions [Details]
Record status:
current
Accession:
RCV000008726.11

Allele description [Variation Report for NM_001077401.2(ACVRL1):c.1232G>A (p.Arg411Gln)]

NM_001077401.2(ACVRL1):c.1232G>A (p.Arg411Gln)

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_001077401.2(ACVRL1):c.1232G>A (p.Arg411Gln)
HGVS:
  • NC_000012.12:g.51916219G>A
  • NG_009549.1:g.13802G>A
  • NM_000020.2:c.1232G>A
  • NM_001077401.2:c.1232G>A
  • NP_000011.2:p.Arg411Gln
  • NP_001070869.1:p.Arg411Gln
  • LRG_543t1:c.1232G>A
  • LRG_543:g.13802G>A
  • LRG_543p1:p.Arg411Gln
  • NC_000012.11:g.52310003G>A
  • NM_001077401.1:c.1232G>A
  • P37023:p.Arg411Gln
Protein change:
R411Q; ARG411GLN
Links:
UniProtKB: P37023#VAR_006213; OMIM: 601284.0001; dbSNP: rs121909284
NCBI 1000 Genomes Browser:
rs121909284
Molecular consequence:
  • NM_000020.2:c.1232G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077401.2:c.1232G>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
SCV000028935OMIMno assertion criteria providedPathogenic
(Apr 1, 2004)
germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

SCV000206819Blueprint Geneticsno assertion criteria providedPathogenic
(Oct 6, 2014)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000552399Invitaecriteria provided, single submitter
Pathogenic
(Oct 6, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000602399ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Mar 11, 2020)
germlineclinical testing

Citation Link,

SCV000893308Fulgent Genetics,Fulgent Geneticscriteria provided, single submitter
Pathogenic
(Oct 31, 2018)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000928397Laboratory of Medical Genetics, National & Kapodistrian University of Athenscriteria provided, single submitter
Pathogenic
(Nov 20, 2018)
de novoclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001439399NIHR 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

Citations

PubMed

Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.

Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, Guttmacher AE, Jackson CE, Attisano L, Kucherlapati R, Porteous ME, Marchuk DA.

Nat Genet. 1996 Jun;13(2):189-95.

PubMed [citation]
PMID:
8640225

Update on molecular diagnosis of hereditary hemorrhagic telangiectasia.

Richards-Yutz J, Grant K, Chao EC, Walther SE, Ganguly A.

Hum Genet. 2010 Jul;128(1):61-77. doi: 10.1007/s00439-010-0825-4. Epub 2010 Apr 23.

PubMed [citation]
PMID:
20414677
See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000028935.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Johnson et al. (1996) identified a 1232G-A transition in the ACVRL1 gene that was predicted to result in an arg411-to-gln (R411Q) substitution.

In a French patient with HHT2, Lesca et al. (2004) identified the R411Q mutation.

In a 26-year-old woman with familial hereditary hemorrhagic telangiectasia-related primary pulmonary hypertension (see 600376), Harrison et al. (2003) identified the R411Q mutation.

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

From Blueprint Genetics, SCV000206819.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Invitae, SCV000552399.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine with glutamine at codon 411 of the ACVRL1 protein (p.Arg411Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs121909284, ExAC 0.01%). This variant has been reported in the literature co-segregating in a family with hereditary hemorrhagic telangiectasia (HHT) (PMID: 8640225) as well as in multiple unrelated individuals affected with HHT (PMID: 15024723, 20414677, 23805858). ClinVar contains an entry for this variant (Variation ID: 8243). Experimental studies have shown that this missense change causes a lack of response to BMP9 stimulation and protein mislocalization disrupting ACVRL1 protein function (PMID: 20501893, 14684682). Two other different missense substitution at this codon (p.Arg411Pro, p.Arg411Trp) have been determined to be pathogenic (PMID: 15024723, 20501893). This suggests that the arginine residue is critical for ACVRL1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000602399.2

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

Description

The ACVRL1 c.1232G>A; p.Arg411Gln variant (rs121909284) has been reported in ClinVar (Variation ID: 8243), and described in the literature in multiple families with hereditary hemorrhagic telangiectasia (HHT) (see HHT database link and references therein). Additionally, this variant has been shown to have defective BMP9 ligand signaling (Ricard 2010). The arginine at codon 411 is a highly conserved residue located in the protein kinase domain, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Link to ARUP HHT database: http://arup.utah.edu/database/ACVRL1/ACVRL1_display.php Link to ClinVar for p.Arg411Gln: https://www.ncbi.nlm.nih.gov/clinvar/variation/8243/ Ricard N et al. (2010) Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 116(9):1604-12.

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

From Fulgent Genetics,Fulgent Genetics, SCV000893308.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV000928397.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

PM1, PM5, PP2, PP3, PP4, PP5

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

From NIHR Bioresource Rare Diseases, University of Cambridge, SCV001439399.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (2)

Description

PS3+PM2+PP4+PP5

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Jul 10, 2021

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