NM_000020.2(ACVRL1):c.1120C>T (p.Arg374Trp) AND Telangiectasia, hereditary hemorrhagic, type 2

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 24, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000008733.10

Allele description [Variation Report for NM_000020.2(ACVRL1):c.1120C>T (p.Arg374Trp)]

NM_000020.2(ACVRL1):c.1120C>T (p.Arg374Trp)

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.1120C>T (p.Arg374Trp)
HGVS:
  • NC_000012.12:g.51916107C>T
  • NG_009549.1:g.13690C>T
  • NM_000020.2:c.1120C>T
  • NM_001077401.2:c.1120C>T
  • NP_000011.2:p.Arg374Trp
  • NP_001070869.1:p.Arg374Trp
  • LRG_543t1:c.1120C>T
  • LRG_543:g.13690C>T
  • LRG_543p1:p.Arg374Trp
  • NC_000012.11:g.52309891C>T
  • NP_000011.2:p.R374W
  • P37023:p.Arg374Trp
Protein change:
R374W; ARG374TRP
Links:
UniProtKB: P37023#VAR_006211; OMIM: 601284.0007; dbSNP: rs28936401
NCBI 1000 Genomes Browser:
rs28936401
Molecular consequence:
  • NM_000020.2:c.1120C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077401.2:c.1120C>T - 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
SCV000028942OMIMno assertion criteria providedPathogenic
(Jun 1, 2008)
germlineliterature only

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

SCV000552398Invitaecriteria provided, single submitter
Pathogenic
(Oct 24, 2020)
germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV000893307Fulgent Genetics,Fulgent Geneticscriteria provided, single submitter
Pathogenic
(Oct 31, 2018)
unknownclinical testing

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

SCV001439395NIHR 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 providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes4not providednot providednot providednot providedresearch
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.

Kjeldsen AD, Brusgaard K, Poulsen L, Kruse T, Rasmussen K, Green A, Vase P.

Am J Med Genet. 2001 Feb 1;98(4):298-302.

PubMed [citation]
PMID:
11170071

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.

Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V, Gruenig E, Kermeen F, Halme M, Räisänen-Sokolowski A, Laitinen T, Morrell NW, Trembath RC.

J Med Genet. 2003 Dec;40(12):865-71. Erratum in: J Med Genet. 2004 Jul;41(7):576.

PubMed [citation]
PMID:
14684682
PMCID:
PMC1735342
See all PubMed Citations (17)

Details of each submission

From OMIM, SCV000028942.2

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

Description

In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Kjeldsen et al. (2001) identified an 1120C-T transition in exon 8 of the ALK1 gene, resulting in an arg374-to-trp (R374W) substitution. No affected patients had pulmonary arteriovenous malformations, and only 1 patient had a history of severe gastrointestinal bleeding.

In a population-based study of primarily French HHT2 patients, Lesca et al. (2008) showed that the R374W mutation associated with a shared ancestral haplotype in a subset of patients, suggesting a founder effect with the mutation arising approximately 300 years ago. In other patients, the mutation was related to different independent mutation events.

In a 41-year-old woman with hereditary hemorrhagic telangiectasis-related pulmonary arterial hypertension (see 600376), Harrison et al. (2003) identified the R374W mutation. The patient had an atrial septal defect repaired before the onset of significantly raised pulmonary artery pressure, and also had a sib with primary pulmonary hypertension (see 178600).

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

From Invitae, SCV000552398.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (13)

Description

This sequence change replaces arginine with tryptophan at codon 374 of the ACVRL1 protein (p.Arg374Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals and families affected with hereditary hemorrhagic telangiectasia (HHT) (PMID: 9245985, 23722869,15375013, 22991266, 15065824, 23805858). ClinVar contains an entry for this variant (Variation ID: 8249). A different missense substitution at this codon (p.Arg374Gln) has been determined to be pathogenic (PMID: 12700602, 18285823, 21158752, 25970827). This suggests that the arginine residue is critical for ACVRL1 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this variant affects several aspects of protein function (PMID: 20501893, 16282348, 15375013). For these reasons, this variant has been classified as Pathogenic.

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

From Fulgent Genetics,Fulgent Genetics, SCV000893307.1

#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 NIHR Bioresource Rare Diseases, University of Cambridge, SCV001439395.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedresearch PubMed (2)

Description

PS3+PM2+PP4+PP5

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided4not providednot providednot provided

Last Updated: May 10, 2021

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