NM_000020.3(ACVRL1):c.1010T>C (p.Leu337Pro) AND Telangiectasia, hereditary hemorrhagic, type 2

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Feb 12, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000857241.2

Allele description [Variation Report for NM_000020.3(ACVRL1):c.1010T>C (p.Leu337Pro)]

NM_000020.3(ACVRL1):c.1010T>C (p.Leu337Pro)

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.1010T>C (p.Leu337Pro)
HGVS:
  • NC_000012.12:g.51915462T>C
  • NG_009549.1:g.13045T>C
  • NM_000020.3:c.1010T>CMANE SELECT
  • NM_001077401.2:c.1010T>C
  • NP_000011.2:p.Leu337Pro
  • NP_001070869.1:p.Leu337Pro
  • LRG_543t1:c.1010T>C
  • LRG_543:g.13045T>C
  • NC_000012.11:g.52309246T>C
  • NM_000020.2:c.1010T>C
  • p.(Leu337Pro)
Protein change:
L337P
Links:
dbSNP: rs1592224349
NCBI 1000 Genomes Browser:
rs1592224349
Molecular consequence:
  • NM_000020.3:c.1010T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077401.2:c.1010T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000999828Center of Genomic medicine, Geneva,University Hospital of Genevacriteria provided, single submitter
Likely pathogenic
(Sep 14, 2018)
germlineclinical testing

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

SCV001541730Invitaecriteria provided, single submitter
Uncertain significance
(Feb 12, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.

Lesca G, Plauchu H, Coulet F, Lefebvre S, Plessis G, Odent S, Rivière S, Leheup B, Goizet C, Carette MF, Cordier JF, Pinson S, Soubrier F, Calender A, Giraud S; French Rendu-Osler Network..

Hum Mutat. 2004 Apr;23(4):289-99.

PubMed [citation]
PMID:
15024723
See all PubMed Citations (4)

Details of each submission

From Center of Genomic medicine, Geneva,University Hospital of Geneva, SCV000999828.1

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

From Invitae, SCV001541730.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces leucine with proline at codon 337 of the ACVRL1 protein (p.Leu337Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15024723, 16690726). ClinVar contains an entry for this variant (Variation ID: 695029). 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

Last Updated: Apr 12, 2021

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