NM_000020.3(ACVRL1):c.830C>G (p.Thr277Arg) AND Telangiectasia, hereditary hemorrhagic, type 2

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jul 10, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001262082.2

Allele description [Variation Report for NM_000020.3(ACVRL1):c.830C>G (p.Thr277Arg)]

NM_000020.3(ACVRL1):c.830C>G (p.Thr277Arg)

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.830C>G (p.Thr277Arg)
HGVS:
  • NC_000012.12:g.51915282C>G
  • NG_009549.1:g.12865C>G
  • NM_000020.3:c.830C>GMANE SELECT
  • NM_001077401.2:c.830C>G
  • NP_000011.2:p.Thr277Arg
  • NP_001070869.1:p.Thr277Arg
  • LRG_543t1:c.830C>G
  • LRG_543:g.12865C>G
  • NC_000012.11:g.52309066C>G
  • NM_000020.2:c.830C>G
Protein change:
T277R
Links:
Molecular consequence:
  • NM_000020.3:c.830C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077401.2:c.830C>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
SCV001439469NIHR Bioresource Rare Diseases, University of Cambridgecriteria provided, single submitter
Likely pathogenic
(Jan 1, 2018)
unknownresearch

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

SCV001545882Invitaecriteria provided, single submitter
Uncertain significance
(Jul 10, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes1not providednot providednot providednot providedresearch

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
See all PubMed Citations (3)

Details of each submission

From NIHR Bioresource Rare Diseases, University of Cambridge, SCV001439469.1

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

Description

PM2+PM1+PP4

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

From Invitae, SCV001545882.1

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

Description

This sequence change replaces threonine with arginine at codon 277 of the ACVRL1 protein (p.Thr277Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Thr277 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic ( PMID: 25970827, 20414677, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Apr 12, 2021

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