NM_000020.3(ACVRL1):c.1427C>G (p.Pro476Arg) AND Telangiectasia, hereditary hemorrhagic, type 2

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: May 15, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001035910.2

Allele description [Variation Report for NM_000020.3(ACVRL1):c.1427C>G (p.Pro476Arg)]

NM_000020.3(ACVRL1):c.1427C>G (p.Pro476Arg)

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.1427C>G (p.Pro476Arg)
HGVS:
  • NC_000012.12:g.51920808C>G
  • NG_009549.1:g.18391C>G
  • NM_000020.3:c.1427C>GMANE SELECT
  • NM_001077401.2:c.1427C>G
  • NP_000011.2:p.Pro476Arg
  • NP_001070869.1:p.Pro476Arg
  • LRG_543t1:c.1427C>G
  • LRG_543:g.18391C>G
  • NC_000012.11:g.52314592C>G
  • NM_000020.2:c.1427C>G
Protein change:
P476R
Links:
Molecular consequence:
  • NM_000020.3:c.1427C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077401.2:c.1427C>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
SCV001199250Invitaecriteria provided, single submitter
Uncertain significance
(May 15, 2019)
germlineclinical testing

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

SCV001439403NIHR 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 providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes1not providednot providednot providednot providedresearch

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

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
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001199250.2

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

Description

This sequence change replaces proline with arginine at codon 476 of the ACVRL1 protein (p.Pro476Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual 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. 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

From NIHR Bioresource Rare Diseases, University of Cambridge, SCV001439403.1

#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

Last Updated: Apr 12, 2021

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