rs863223414

Positions:

• chr12-51913237-G-A
• chr12-51913237-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.200G>A​(p.Arg67Gln) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.46

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 16 ACMG points.

• PM1: In a strand (size 8) in uniprot entity ACVL1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr12-51913236-C-T is described in Lovd as [Pathogenic].
• 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, 0.779
• PP5: Variant 12-51913237-G-A is Pathogenic according to our data. Variant chr12-51913237-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.200G>A	p.Arg67Gln	missense_variant	3/10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.200G>A	p.Arg67Gln	missense_variant	3/10	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 19, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate complete loss of signaling (PMID: 10187774); 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: 22028876, 14684682, 9245985, 23722869, 15880681, 22553411, 11484689, 16429404, 27860447, 17786384, 18498373, 10187774, 31400083, 32573726, 35628811, 16706966, 32503579) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 31, 2023	PP1, PP4, PM2_supporting, PM5, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 18, 2017	The ACVRL1 c.200G>A; p.Arg67Gln variant (rs863223414) has been reported in multiple unrelated individuals and families with hereditary hemorrhagic telangiectasia (Berg 1997, Canzonieri 2014, Giordano 2006, Lenato 2006, Olivieri 2007, Schulte 2005). This variant is reported in the ClinVar database (Variation ID: 212803), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The arginine at codon 67 is highly conserved, and computational algorithms (SIFT, MutationTaster, Align GVGD) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg67Gln: https://www.ncbi.nlm.nih.gov/clinvar/variation/212803/ Berg JN et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997 Jul;61(1):60-7. Canzonieri C et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genet Med. 2014 Jan;16(1):3-10. Giordano P et al. Screening for children from families with Rendu-Osler-Weber disease: from geneticist to clinician. J Thromb Haemost. 2006 Jun;4(6):1237-45. Lenato GM et al. DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. Hum Mutat. 2006 Feb;27(2):213-4. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52(10):820-9. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595. -

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM5+PS4+PP4+PS3_Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 67 of the ACVRL1 protein (p.Arg67Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemorrhagic telangiectasia (PMID: 9245985, 15880681, 16706966, 17786384, 18498373, 23722869). ClinVar contains an entry for this variant (Variation ID: 212803). 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 80%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 10187774, 14684682). This variant disrupts the p.Arg67 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17786384, 18285823, 22377182, 22553411). 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. -
Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PM2+PP4+PP5 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The p.R67Q pathogenic mutation (also known as c.200G>A), located in coding exon 2 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 200. The arginine at codon 67 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been identified in multiple unrelated individuals with hereditary hemorrhagic telangiectasia (Lenato GM et al. Hum. Mutat., 2006 Feb;27:213-4; Giordano P et al. J. Thromb. Haemost., 2006 Jun;4:1237-45; Olivieri C et al. J. Hum. Genet., 2007 Sep;52:820-9; Zhao Y et al. Mol Genet Genomic Med. 2019 09;7(9):e893). An in vitro functional study demonstrated that this mutation abolished protein signaling (Lux A et al. J. Biol. Chem., 1999 Apr;274:9984-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	Benign	0.21
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Benign	1.5	.;L;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.8	D;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.12	T;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;T
Polyphen		0.15	.;B;.;.
Vest4		0.23, 0.16
MutPred		0.89		Loss of methylation at R67 (P = 0.0435);Loss of methylation at R67 (P = 0.0435);.;.;
MVP		0.98
MPC		0.68
ClinPred		0.62	D
GERP RS		4.9
Varity_R		0.39
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs863223414; hg19: chr12-52307021; COSMIC: COSV101187805; COSMIC: COSV101187805;