12-51920832-G-A

Position:

• chr12-51920832-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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 chr12-51920832-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1512139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACVRL1. . Gene score misZ 2.4458 (greater than the threshold 3.09). Trascript score misZ 3.182 (greater than threshold 3.09). GenCC has associacion of gene with hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 2.
• 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 id is 212796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51920832-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.1451G>A	p.Arg484Gln	missense_variant	10/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1451G>A	p.Arg484Gln	missense_variant	10/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 04, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Sep 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. -

Pulmonary arterial hypertension Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 04, 2016

- -

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

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

-

- -

Epistaxis;C2973725:Pulmonary arterial hypertension Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 24, 2015

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 25, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2022

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	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	0.73	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
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	D
GERP RS		4.4
Varity_R		0.87
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs863223408; hg19: chr12-52314616; COSMIC: COSV101188037; COSMIC: COSV101188037;