NM_000020.3(ACVRL1):c.231C>G (p.Cys77Trp) AND Telangiectasia, hereditary hemorrhagic, type 2

Clinical significance:Pathogenic (Last evaluated: Aug 8, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001224004.1

Allele description [Variation Report for NM_000020.3(ACVRL1):c.231C>G (p.Cys77Trp)]

NM_000020.3(ACVRL1):c.231C>G (p.Cys77Trp)

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.231C>G (p.Cys77Trp)
HGVS:
  • NC_000012.12:g.51913268C>G
  • NG_009549.1:g.10851C>G
  • NM_000020.3:c.231C>GMANE SELECT
  • NM_001077401.2:c.231C>G
  • NP_000011.2:p.Cys77Trp
  • NP_001070869.1:p.Cys77Trp
  • LRG_543t1:c.231C>G
  • LRG_543:g.10851C>G
  • NC_000012.11:g.52307052C>G
  • NM_000020.2:c.231C>G
Protein change:
C77W
Molecular consequence:
  • NM_000020.3:c.231C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077401.2:c.231C>G - 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
SCV001396177Invitaecriteria provided, single submitter
Pathogenic
(Aug 8, 2019)
germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Novel missense and frameshift mutations in the activin receptor-like kinase-1 gene in hereditary hemorrhagic telangiectasia. Mutations in brief no. 164. Online.

Klaus DJ, Gallione CJ, Anthony K, Yeh EY, Yu J, Lux A, Johnson DW, Marchuk DA.

Hum Mutat. 1998;12(2):137.

PubMed [citation]
PMID:
10694922

Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations.

Prigoda NL, Savas S, Abdalla SA, Piovesan B, Rushlow D, Vandezande K, Zhang E, Ozcelik H, Gallie BL, Letarte M.

J Med Genet. 2006 Sep;43(9):722-8. Epub 2006 May 11.

PubMed [citation]
PMID:
16690726
PMCID:
PMC2564570
See all PubMed Citations (10)

Details of each submission

From Invitae, SCV001396177.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

This sequence change replaces cysteine with tryptophan at codon 77 of the ACVRL1 protein (p.Cys77Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of hereditary hemorrhagic telangiectasia (HHT) (PMID: 10694922, 16690726, Invitae). This variant has been reported to affect ACVRL1 protein function (PMID: 20501893, 14684682). This variant disrupts the p.Cys77 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 26176610, 17786384), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue located within the ACVRL1 protein ectodomain. Cysteine residues in this domain of ACVRL1 are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 22028876, 22718755, 22799562). In addition, missense substitutions within the ACVRL1 ectodomain affecting cysteine residues are overrepresented in patients with HHT (PMID: 20501893, 26176610 and www.hhtmutation.org). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 7, 2021

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