NM_000020.3(ACVRL1):c.653G>C (p.Arg218Pro) AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 14, 2016
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000458880.7

Allele description [Variation Report for NM_000020.3(ACVRL1):c.653G>C (p.Arg218Pro)]

NM_000020.3(ACVRL1):c.653G>C (p.Arg218Pro)

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.653G>C (p.Arg218Pro)

HGVS:

NC_000012.12:g.51914466G>C
NG_009549.1:g.12049G>C
NM_000020.3:c.653G>CMANE SELECT
NM_001077401.2:c.653G>C
NP_000011.2:p.Arg218Pro
NP_000011.2:p.Arg218Pro
NP_001070869.1:p.Arg218Pro
LRG_543t1:c.653G>C
LRG_543:g.12049G>C
LRG_543p1:p.Arg218Pro
NC_000012.11:g.52308250G>C
NM_000020.2:c.653G>C

Protein change:

R218P

Links:

dbSNP: rs779287554

NCBI 1000 Genomes Browser:

rs779287554

Molecular consequence:

NM_000020.3:c.653G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001077401.2:c.653G>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000552395	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 14, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23919827, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000552395

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 14, 2016)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical and genetic characteristics of Chinese patients with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension.

Chen YJ, Yang QH, Liu D, Liu QQ, Eyries M, Wen L, Wu WH, Jiang X, Yuan P, Zhang R, Soubrier F, Jing ZC.

Eur J Clin Invest. 2013 Oct;43(10):1016-24. doi: 10.1111/eci.12138. Epub 2013 Aug 6.

PubMed [citation]

PMID:: 23919827

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000552395.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. This sequence change replaces arginine with proline at codon 218 of the ACVRL1 protein (p.Arg218Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ACVRL1-related disease. A different variant (c.653_654delinsCC) giving rise to the same protein effect observed here (p.Arg218Pro) has been reported in two related individuals affected with hereditary haemorrhagic telangiectasia (PMID: 23919827), indicating that this residue may be critical for protein function. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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