NM_000020.3:c.1231C>T

Variant names:

• chr12-51916218-C-T
• rs121909287
• NM_000020.3:c.1231C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1231C>T​(p.Arg411Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R411Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 1.45
• Publications: 25 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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 chr12-51916219-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8243.Status of the report is reviewed_by_expert_panel, 3 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, 0.988
• PP5: Variant 12-51916218-C-T is Pathogenic according to our data. Variant chr12-51916218-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8251.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	c.1231C>T	p.Arg411Trp	missense_variant	Exon 8 of 10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1231C>T	p.Arg411Trp	missense_variant	Exon 8 of 10	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.000151 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:5 Other:1

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in ACVRL1 is predicted to replace arginine with tryptophan at codon 411 (p.(Arg411Trp)). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the protein kinase domain. There is a large physicochemical difference between arginine and tryptophan. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in multiple probands with a clinical diagnosis of hereditary haemorrhagic telangiectasia (HHT) and pulmonary hypertension, and segregates with HHT in multiple families (PMID: 11484689, 15024723). BMP9 ligand binding assays in cell lines showed defective signalling indicating that this variant impacts protein function (PMID: 20501893). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Another missense variant c.1232G>A, p.Arg411Gln in the same codon has been classified as pathogenic for HHT (ClinVar ID: 8243). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM5, PS3_Supporting, PM2_Supporting, PP1, PP3. -

Apr 04, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACVRL1 c.1231C>T; p.Arg411Trp variant (rs121909287) is reported in multiple individuals with hereditary hemorrhagic telangiectasia (HHT) and/or pulmonary arterial hypertension (PAH), and has been shown to co-segregate with disease (Abdalla 2003, Piao 2016, Trembath 2001, see link to ACVRL1 database and references therein). This variant is located in the catalytic domain of ACVRL1 and functional data indicate that it leads to impaired BMP9 signaling (Alaa El Din 2015, Piao 2016, Ricard 2010). The arginine at codon 411 has been described as a mutation hotspot (Lesca 2004), as both Arg411Pro and Arg411Gln are also frequently observed in HHT patients, both in our laboratory and as reported in the published literature (Lesca 2004, see ACVRL1 database and references therein). The p.Arg411Trp variant is also reported in ClinVar (Variation ID: 8251). It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The ariginine at codon 411 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict this variant to be deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to ACVRL1 database: http://arup.utah.edu/database/ACVRL1/ACVRL1_display.php Abdalla SA et al. Visceral manifestations in hereditary haemorrhagic telangiectasia type 2. J Med Genet. 2003 Jul;40(7):494-502. Alaa El Din F et al. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. PLoS One. 2015 Jul 15;10(7):e0132111. Hume AN et al. Retention in the endoplasmic reticulum is the underlying mechanism of some hereditary haemorrhagic telangiectasia type 2 ALK1 missense mutations. Mol Cell Biochem. 2013 Jan;373(1-2):247-57. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. Piao C et al. Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture. Clin Sci (Lond). 2016 Sep 1;130(17):1559-69. Ricard N et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010 Sep 2;116(9):1604-12. Trembath RC et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001 Aug 2;345(5):325-34. -

Jun 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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 -

-

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as not provided and reported on 04-27-2017 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Philip Payne PhD, FACMI from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Jan 20, 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 tryptophan, which is neutral and slightly polar, at codon 411 of the ACVRL1 protein (p.Arg411Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemorrhagic telangiectasia (PMID: 11484689, 15024723, 15880681). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8251). 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: 20501893, 23124896, 26176610). 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: 8640225, 14684682, 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. -

not provided Pathogenic:2

Oct 22, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PM1, PM2, PS3, PS4_moderate -

Feb 17, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals from various ethnic backgrounds with HHT and/or PAH (Trembath et al., 2001; Abdalla et al., 2003; Lesca et al., 2004; Kuehl et al., 2005; Letteboer et al., 2005; Schulte et al., 2005; Piao et al., 2016; Han et al., 2020; Shovlin et al., 2020; Kitayama et al., 2021; Zhang et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant results in defective BMP9 response and impaired ALK1 activity due to abnormal ALK1 trafficking (Ricard et al., 2010; Hume et al., 2013); 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: 15879500, 16542389, 25312062, 15024723, 26176610, 27316748, 15517393, 15880681, 15712270, 12114496, 12700602, 23124896, 28823282, 30578397, 32573726, 20501893, 29631995, 32300199, 32954380, 34966542, 32503579, 34872578, 11484689) -

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia Pathogenic:1

Jun 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype Pathogenic:1

Apr 14, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R411W pathogenic mutation (also known as c.1231C>T), located in coding exon 7 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1231. The arginine at codon 411 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been identified in multiple individuals with hereditary hemorrhagic telangiectasia (HHT) with segregation with disease in a few families. In addition, this mutation has also been reported in association with pulmonary arterial hypertension with or without HHT (Trembath RC et al. N. Engl. J. Med., 2001 Aug;345:325-34; Abdalla SA et al. Eur. J. Hum. Genet., 2003 Apr;11:279-87; Zhang GS et al. Chin. Med. J., 2004 Jun;117:808-12; Song J et al. Clin Sci (Lond). 2016 11;130(22):2043-2052; Zhu N et al. Circ Genom Precis Med. 2018 04;11(4):e001887). In vitro functional studies indicate that mutations at this codon 411 impair ALK1 activity (Ricard N et al. Blood, 2010 Sep;116:1604-12; Alaa El Din F et al. PLoS ONE, 2015 Jul;10:e0132111). 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	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.57	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.;.
PhyloP100		1.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.92
MutPred		0.94		Gain of catalytic residue at W406 (P = 0.0784);.;.;
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.97
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909287; hg19: chr12-52310002;