rs863223408

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000020.3(ACVRL1):c.1451G>A(p.Arg484Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R484G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

ACVRL1
NM_000020.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.99

Publications

15 publications found

Variant links:

Genes affected

ACVRL1 (HGNC:175): (activin A receptor like type 1) This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hemorrhagic telangiectasia type 2, also known as Rendu-Osler-Weber syndrome 2. [provided by RefSeq, Jul 2008]

ACVRL1 Gene-Disease associations (from GenCC):

telangiectasia, hereditary hemorrhagic, type 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
hereditary hemorrhagic telangiectasia
Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACVRL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000020.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-51920831-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 426037.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the ACVRL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 203 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.4458 (below the threshold of 3.09). Trascript score misZ: 3.182 (above the threshold of 3.09). GenCC associations: The gene is linked to telangiectasia, hereditary hemorrhagic, type 2, hereditary hemorrhagic telangiectasia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 12-51920832-G-A is Pathogenic according to our data. Variant chr12-51920832-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 212796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3 link	c.1451G>A	p.Arg484Gln	missense_variant	Exon 10 of 10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9 link	c.1451G>A	p.Arg484Gln	missense_variant	Exon 10 of 10	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2

Pathogenic:5

Sep 26, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Pathogenic. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PP2+PS3_Supporting+PS4+PM5_Strong+PP1_Moderate+PP4_Moderate -

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 484 of the ACVRL1 protein (p.Arg484Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary haemorrhagic telangiectasia or pulmonary arterial hypertension (PMID: 15687131, 17786384, 18159113, 21378382, 22632830, 23298310, 23919827). ClinVar contains an entry for this variant (Variation ID: 212796). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 20501893). This variant disrupts the p.Arg484 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11484689, 16540754, 18498373, 20056902, 20501893, 23124896, 27316748). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not specified

Pathogenic:1

Dec 04, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pulmonary arterial hypertension

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia

Pathogenic:1

Rare Disease Genomics Group, St George's University of London

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Epistaxis;C2973725:Pulmonary arterial hypertension

Pathogenic:1

Nov 24, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Feb 25, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that variants in residue 484, which is located in the highly conserved NANDOR box region, cause defective signaling with the BMP9 ligand (Ricard et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21378382, 17786384, 23919827, 22632830, 18159113, 23298310, 29631995, 26387786, 20501893, 27587546, 31630786, 30578397, 30578106, 31511490, 32170914, 32581362, 34966542, 15687131) -

Cardiovascular phenotype

Pathogenic:1

Aug 26, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R484Q pathogenic mutation (also known as c.1451G>A), located in coding exon 9 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1451. The arginine at codon 484 is replaced by glutamine, an amino acid with highly similar properties. In one study of 18 children with pulmonary arterial hypertension (PAH), this mutation was detected in an individual with idiopathic PAH, but with no manifestations of hereditary hemorrhagic telangiectasia (HHT) at 5 years old (Harrison RE et al. Circulation, 2005 Feb;111:435-41). This mutation was also reported in a family in which two mutation carriers showed symptoms of PAH and one of HHT; there was also one unaffected mutation carrier in the family (Pfarr N et al. Respir. Res., 2013;14:3). Furthermore, this mutation was described in an individual with PAH and HHT (Chen YJ et al. Eur. J. Clin. Invest., 2013 Oct;43:1016-24). The p.R484Q mutation is located in the intracellular kinase domain in the NANDOR box of the ALK1 protein, and functional studies showed this mutation had no functional activity in response to BMP9, a ligand for ALK1 (Ricard N et al. Blood, 2010 Sep;116:1604-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

0.73

N;.;.

PhyloP100

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;T

Polyphen

1.0

D;.;D

Vest4

0.86

MutPred

0.91

Loss of MoRF binding (P = 0.0549);.;.;

MVP

0.99

MPC

1.7

ClinPred

0.98

GERP RS

4.4

Varity_R

0.87

gMVP

0.94

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over