NM_000020.3:c.1232G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PP1_StrongPS3_SupportingPP4_ModeratePP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000020.3: c.1232G>A variant in ACVRL1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 411 (p.Arg411Gln). The overall minor allele frequency in gnomAD v2.1.1 is 0.000007980 (2/250642 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID:8640225, 31400083, 32300199, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; PMID:32300199). The variant has been reported to segregate with HHT in 8 affected family members from one family (PP1_Strong; PMID:8640225). The computational predictor REVEL gives a score of 0.904, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). Additionally, binding assays in cell lines showed no BMP9 response indicating that this variant impacts protein function (PS3_Supporting; PMID:20501893). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PP1_Strong, PP4_Moderate, PM2_Supporting, PP3, PS3_Supporting (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA119395/MONDO:0010880/135

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACVRL1
NM_000020.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15

Conservation

PhyloP100: 9.99

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3 link	c.1232G>A	p.Arg411Gln	missense_variant	Exon 8 of 10	ENST00000388922.9	NP_000011.2	P37023A0A0S2Z310

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9 link	c.1232G>A	p.Arg411Gln	missense_variant	Exon 8 of 10	1	NM_000020.3	ENSP00000373574.4		P37023

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250642

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135552

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2

Pathogenic:9

Oct 06, 2014

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 11, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACVRL1 c.1232G>A; p.Arg411Gln variant (rs121909284) has been reported in ClinVar (Variation ID: 8243), and described in the literature in multiple families with hereditary hemorrhagic telangiectasia (HHT) (see HHT database link and references therein). Additionally, this variant has been shown to have defective BMP9 ligand signaling (Ricard 2010). The arginine at codon 411 is a highly conserved residue located in the protein kinase domain, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Link to ARUP HHT database: http://arup.utah.edu/database/ACVRL1/ACVRL1_display.php Link to ClinVar for p.Arg411Gln: https://www.ncbi.nlm.nih.gov/clinvar/variation/8243/ Ricard N et al. (2010) Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 116(9):1604-12. -

Jan 01, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3+PM2+PP4+PP5 -

Jan 13, 2025

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 411 of the ACVRL1 protein (p.Arg411Gln). This variant is present in population databases (rs121909284, gnomAD 0.007%). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 8640225, 15024723, 20414677, 23805858). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8243). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 14684682, 20501893). This variant disrupts the p.Arg411 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15024723, 20501893). 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. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2024

ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000020.3: c.1232G>A variant in ACVRL1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 411 (p.Arg411Gln). The overall minor allele frequency in gnomAD v2.1.1 is 0.000007980 (2/250642 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID: 8640225, 31400083, 32300199, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; PMID: 32300199). The variant has been reported to segregate with HHT in 8 affected family members from one family (PP1_Strong; PMID: 8640225). The computational predictor REVEL gives a score of 0.904, which is above the threshold of greater than or equal to 0.644, evidence that correlates with impact to ACVRL1 function (PP3). Additionally, binding assays in cell lines showed no BMP9 response indicating that this variant impacts protein function (PS3_Supporting; PMID: 20501893). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PP1_Strong, PP4_Moderate, PM2_Supporting, PP3, PS3_Supporting (specification version 1.0.0; 1/4/2024). -

Nov 20, 2018

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a glutamine (exon 8). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif. This variant at residue 411 was shown to be essential for the function of the kinase domain (PMID: 20501893). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Alternate changes at the same residue, to tryptophan and proline, have previously been reported in multiple patients with HHT (ClinVar, HGMD, LOVD, PMID: 15024723). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been classified as pathogenic and reported in multiple patients with HHT (ClinVar, HGMD, LOVD, PMID: 8640225, PMID: 31400083). (P) 0901 - Strong evidence for segregation with disease. The variant has been reported to segregate with disease in HHT families (PMID: 8640225, PMID: 31400083). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies in transfected cells demonstrated that the variant resulted in a reduced ability of ACVRL1 to bind its ligand BMP9 (PMID: 20501893). (P) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided

Pathogenic:4

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM1, PM2_supporting, PS3, PS4 -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate reduced ACVRL1 activity (Gu et al., 2006; Ricard et al., 2010; Laux et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); 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: 17384219, 15521985, 16754821, 25892364, 34872578, 20501893, 11802521, 12700602, 14684682, 18673552, 16540754, 16752392, 16470787, 16429404, 16282348, 23863480, 15611116, 20067780, 28652319, 15024723, 9245985, 15880681, 12114496, 29743074, 31630786, 32503579, 34008892, 32300199, 33201366, 32573726, 8640225) -

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia

Pathogenic:1

Apr 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype

Pathogenic:1

Oct 19, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R411Q pathogenic mutation (also known as c.1232G>A), located in coding exon 7 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1232. The arginine at codon 411 is replaced by glutamine, an amino acid with highly similar properties.This mutation has been detected in multiple individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) (Gedge F et al. J Molec Diag. 2007;9(2):258-265; Tørring PM et al. PLoS ONE, 2014 Mar;9:e90272), including an individual with a history of pulmonary hypertension (Harrison RE et al. J. Med. Genet., 2003 Dec;40:865-71). This amino acid position is located in the intracellular kinase domain, and a functional study found that p.R411Q interferes with downstream signaling activity of the protein (Ricard N et al. Blood. 2010: 116(9):1604-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Two additional disease causing alterations have been described at the same codon, p.R411P and p.R411W (Gedge F et al. J Molec Diag. 2007;9(2):258-265; Trembath RC et al. N. Engl. J. Med., 2001 Aug;345:325-34). 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

0.77

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;.;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

M;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.90

MutPred

0.96

Loss of MoRF binding (P = 0.0867);.;.;

MVP

0.97

MPC

1.7

ClinPred

1.0

GERP RS

4.8

Varity_R

0.97

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over