chr12-51913236-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000020.3(ACVRL1):c.199C>T(p.Arg67Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000252 in 1,589,500 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ACVRL1
NM_000020.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -0.147

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 17 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;

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 hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 2.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 12-51913236-C-T is Pathogenic according to our data. Variant chr12-51913236-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 426010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51913236-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3 link	c.199C>T	p.Arg67Trp	missense_variant	Exon 3 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.199C>T	p.Arg67Trp	missense_variant	Exon 3 of 10	1	NM_000020.3	ENSP00000373574.4		P37023

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000209

AC:

AN:

1437362

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712678

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:

0.0000195

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2

Pathogenic:3

Apr 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACVRL1 c.199C>T; p.Arg67Trp variant (rs1085307405) has been described in the medical literature in several individuals and families diagnosed with hereditary hemorrhagic telangiectasia (see Ha 2012, Olivieri 2002, Samol 2012) as well as one individual diagnosed with pulmonary arterial hypertension (Zhu 2019). This variant is also reported in the ClinVar database (Variation ID: 426010). It is only found on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant occurs in a functional domain (Scotti 2011), and computational analyses predict that this variant is deleterious (REVEL: 0.723). Based on available information, this variant is considered to be pathogenic. REFERENCES Ha M et al. Gastric angiodysplasia in a hereditary hemorrhagic telangiectasia type 2 patient. World J Gastroenterol. 2012 Apr 21;18(15):1840-4. PMID: 22553411. Olivieri C et al. Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia. J Med Genet. 2002 Jul;39(7):E39. PMID: 12114496. Samol A et al. A rare cause of fatal right ventricular cardiac decompensation. Cardiovasc Pathol. 2012 Nov-Dec;21(6):515-8.. PMID: 22377182. Scotti C et al. Bioinformatic analysis of pathogenic missense mutations of activin receptor like kinase 1 ectodomain. PLoS One. 2011;6(10):e26431. PMID: 22028876. Zhu N et al. Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension. Genome Med. 2019 Nov 14;11(1):69. PMID: 31727138. -

Aug 27, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 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 tryptophan, which is neutral and slightly polar, at codon 67 of the ACVRL1 protein (p.Arg67Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 12114496, 15712271, 16123970, 22377182, 22553411). ClinVar contains an entry for this variant (Variation ID: 426010). 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%. 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: 9245985, 15880681, 16706966, 17786384, 18498373, 23722869). 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. -

ACVRL1-related disorder

Pathogenic:1

Nov 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACVRL1 c.199C>T variant is predicted to result in the amino acid substitution p.Arg67Trp. This variant has been reported in multiple individuals with hereditary hemorrhagic telangiectasia (HTT) (Olivieri et al. 2002. PubMed ID: 12114496; Ha et al. 2012. PubMed ID: 22553411; Samol et al. 2012. PubMed ID: 22377182) and in a patient with HHT with pulmonary arterial hypertension (Table S3 in Zhu. 2019. PubMed ID: 31727138). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-52307020-C-T) and has been interpreted as pathogenic and likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/426010/). This variant is interpreted as pathogenic. -

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia

Pathogenic:1

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

See cases

Pathogenic:1

Dec 13, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PM1,PM2,PP3,PP4,PP5 -

not provided

Pathogenic:1

Dec 02, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 22028876, 34134972, 22553411, 31727138, 15712271, 16123970, 12114496, 23919827, 15266205, 17786384, 18285823, 16525724, 31455059, 20414677, 22377182) -

Cardiovascular phenotype

Pathogenic:1

Oct 02, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R67W pathogenic mutation (also known as c.199C>T), located in coding exon 2 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 199. The arginine at codon 67 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in multiple individuals with features consistent with, or who met clinical criteria for, hereditary hemorrhagic telangiectasia (HHT) (Olivieri C et al. J. Med. Genet., 2002 Jul;39:E39; Argyriou L et al. Liver Transpl., 2005 Sep;11:1132-5; Ha M et al. World J. Gastroenterol., 2012 Apr;18:1840-4; Samol A et al. Cardiovasc. Pathol.;21:515-8). Another variant at the same codon, p.R67Q (c.200G>A), has also been reported in association with HHT (Berg JN et al. Am. J. Hum. Genet., 1997 Jul;61:60-7; Canzonieri C et al. Genet. Med., 2014 Jan;16:3-10). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

.;D;.;.

Eigen

Benign

0.016

Eigen_PC

Benign

-0.048

FATHMM_MKL

Benign

0.53

LIST_S2

Uncertain

0.89

D;T;D;T

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

1.5

.;L;.;.

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-6.0

D;D;N;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.50, 0.52

MutPred

0.89

Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);.;.;

MVP

0.99

MPC

0.61

ClinPred

0.99

GERP RS

3.9

Varity_R

0.64

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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