rs863223414

Variant names:

• chr12-51913237-G-A
• rs863223414
• NM_000020.3:c.200G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 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 Likely 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:9
• Conservation: PhyloP100: 1.46
• Publications: 10 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 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr12-51913236-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 426010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.779
• PP5: Variant 12-51913237-G-A is Pathogenic according to our data. Variant chr12-51913237-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 212803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000020.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	NM_000020.3	MANE Select	c.200G>A	p.Arg67Gln	missense	Exon 3 of 10	NP_000011.2
	ACVRL1	NM_001077401.2		c.200G>A	p.Arg67Gln	missense	Exon 2 of 9	NP_001070869.1
	ACVRL1	NM_001406487.1		c.200G>A	p.Arg67Gln	missense	Exon 4 of 11	NP_001393416.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	ENST00000388922.9	TSL:1 MANE Select	c.200G>A	p.Arg67Gln	missense	Exon 3 of 10	ENSP00000373574.4
	ACVRL1	ENST00000550683.5	TSL:1	c.242G>A	p.Arg81Gln	missense	Exon 2 of 9	ENSP00000447884.1
	ACVRL1	ENST00000551576.6	TSL:1	c.200G>A	p.Arg67Gln	missense	Exon 4 of 11	ENSP00000455848.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000538 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:4

Jan 01, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2+PP4+PP5

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Nov 24, 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 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). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACVRL1 c.200G>A; p.Arg67Gln variant (rs863223414, ClinVar Variation ID: 212803) 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 absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0536). Based on available information, this variant is considered pathogenic. References: 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. PMID: 9245985 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. PMID 23722869 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. PMID: 16706966 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. PMID: 16429404 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. PMID: 17786384

not provided Pathogenic:3

Mar 19, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP4, PM2_supporting, PM5, PS3, PS4

Dec 26, 2023

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 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)

Cardiovascular phenotype Pathogenic:1

Dec 03, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Hereditary hemorrhagic telangiectasia Pathogenic:1

Feb 06, 2025

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 glutamine at codon 67, p.(Arg67Gln). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments) and is not located in an annotated domain. There is a small physicochemical difference between arginine and glutamine. ACVRL1, in which the variant was identified is a gene significantly constrained for missense variation and where pathogenic missense variants are a common mechanism of disease (ClinVar, gnomAD v4.1). This variant is absent from the population database gnomAD v4.1. Clinvar contains an entry for this variant (Variation ID: 212803). This variant has been reported in multiple probands with a phenotype consistent with hereditary haemorrhagic telangiectasia (HHT; PMID: 16706966, 17786384, 18498373) and it is observed to segregate with disease in multiple families (PMID:16706966). At least one individual with this variant satisfied Curacao criteria, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PMID: 31400083). Functional studies assaying intracellular signalling activity and subcellular protein localisation are supportive of a damaging effect on protein function (PMID: 10187774, 14684682). Computational evidence is uninformative for the missense substitution (REVEL = 0.54). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as PATHOGENIC. Following criteria are met: PM2_Supporting, PP1_Moderate, PP2, PP4_Moderate, PS3_Supporting, PS4

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.54
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.15	B
Vest4		0.23
MutPred		0.89		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
Mutation Taster		=19/81	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863223414; hg19: chr12-52307021; COSMIC: COSV101187805; COSMIC: COSV101187805;