12-51916107-C-T

Position:

chr12-51916107-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000020.3(ACVRL1):c.1120C>T(p.Arg374Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,404 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. R374Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACVRL1
NM_000020.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 3.33

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 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 0 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 chr12-51916108-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 411314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant where missense usually causes diseases, ACVRL1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 12-51916107-C-T is Pathogenic according to our data. Variant chr12-51916107-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3 linkuse as main transcript	c.1120C>T	p.Arg374Trp	missense_variant	8/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9 linkuse as main transcript	c.1120C>T	p.Arg374Trp	missense_variant	8/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461192

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726758

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 25, 2022	PS4 PS3 PM2 PM1 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 374 of the ACVRL1 protein (p.Arg374Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 9245985, 15065824, 15375013, 22991266, 23722869, 23805858). ClinVar contains an entry for this variant (Variation ID: 8249). 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: 15375013, 16282348, 20501893). This variant disrupts the p.Arg374 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12700602, 18285823, 21158752, 25970827). 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, no assertion criteria provided	literature only	OMIM	Jun 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 31, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2022	The ACVRL1 c.1120C>T; p.Arg374Trp variant (rs28936401) has been shown to co-segregate with disease in multiple families affected with symptoms of HHT (Berg 1997, Canzonieri 2014, Harrison 2003, Lesca 2008, Nishida 2012, Ricard 2010, see HHT database link), as well as identified in a number of affected patients by our laboratory. This variant is reported in ClinVar as pathogenic (Variation ID: 8249). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 374 is located in exon 8 of ACVRL1, which has been described as a hotspot for pathogenic variants (Olivieri 2002). Based on available information, this variant is considered to be pathogenic. References: Link to ACVRL1 HHT database: http://arup.utah.edu/database/ACVRL1/ACVRL1_display.php Berg et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997; 61(1): 60-67. Canzonieri et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genet Med. 2014; 16(1): 3-10. Harrison et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003; 40(12): 865-871. Lesca et al. Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients. Eur J Hum Genet. 2008; 16(6): 742-749. Nishida et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012; 158A(11): 2829-2834. Olivieri 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; 39(7): E39. Ricard et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010; 116(9): 1604-1612. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 05, 2021	PM1, PM2, PM5, PP3, PP5 -
Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PS3+PM2+PP4+PP5 -

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2008	- -
Pathogenic, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	-	- -

ACVRL1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 21, 2023

The ACVRL1 c.1120C>T variant is predicted to result in the amino acid substitution p.Arg374Trp. This variant has been documented numerous times in individuals with hereditary hemorrhagic telangiectasia (HHT) (Kitayama et al. 2021. PubMed ID: 34872578; Table S1 in McDonald et al. 2020. PubMed ID: 32300199; Supplementary Table in Nishida et al. 2012. PubMed ID: 22991266). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/8249/). This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2021

Not observed in large population cohorts (gnomAD); Functional studies have demonstrated that the ALK1 protein harboring R374W is unresponsive to BMP9 and TGF-beta signaling and does not induce SMAD1/5 phosphorylation (Gu et al., 2006; Ricard et al., 2010).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 8249; ClinVar); This variant is associated with the following publications: (PMID: 22991266, 14684682, 17786384, 17384219, 16542389, 15517393, 9245985, 11170071, 18285823, 25892364, 26387786, 15065824, 23722869, 15375013, 23805858, 29631995, 31400083, 30578383, 31727138, 32503579, 32573726, 20501893, 16282348) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2022

The p.R374W pathogenic mutation (also known as c.1120C>T), located in coding exon 7 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1120. The arginine at codon 374 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals and families with hereditary hemorrhagic telangiectasia (Berg JN et al. Am. J. Hum. Genet., 1997 Jul;61:60-7; Abdalla SA et al. Eur. J. Hum. Genet., 2003 Apr;11:279-87; Zhao Y et al. Mol Genet Genomic Med. 2019 09;7(9):e893; Shovlin CL et al. Blood. 2020 10;136(17):1907-1918). In addition, this mutation, located in the kinase domain of ACVRL1, showed decreased enzyme activity in in vitro functional studies (Fernandez-L A et al. Hum. Mutat., 2006 Mar;27:295; Gu Y et al. Blood, 2006 Mar;107:1951-4; 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). 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

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;D

Eigen

Benign

0.028

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-8.0

D;D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.93

MutPred

0.95

Loss of methylation at R374 (P = 0.0273);.;.;

MVP

0.85

MPC

1.6

ClinPred

0.94

GERP RS

-0.57

Varity_R

0.97

gMVP

0.94

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

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