12-51916108-G-A

Position:

chr12-51916108-G-A

Variant summary

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

The ENST00000388922.9(ACVRL1):c.1121G>A(p.Arg374Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,480 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R374W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACVRL1
ENST00000388922.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.99

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 ENST00000388922.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

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, 0.983

PP5

Variant 12-51916108-G-A is Pathogenic according to our data. 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. Variant chr12-51916108-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3 linkuse as main transcript	c.1121G>A	p.Arg374Gln	missense_variant	8/10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9 linkuse as main transcript	c.1121G>A	p.Arg374Gln	missense_variant	8/10	1	NM_000020.3	ENSP00000373574	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251110

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461284

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726798

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:

0.0000187

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace arginine with glutamine at codon 374 of the ACVRL1 protein (p.(Arg374Gln)). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the protein kinase domain. There is a small physicochemical difference between arginine and glutamine. The variant is present in a single individual in a large population cohort (1/251,110 alleles in gnomAD v2.1). It is a recurrent variant that has been identified in multiple individuals with a clinical diagnosis of hereditary haemorrhagic telangiectasia (HHT), and segregates with disease in multiple families (PMID: 12700602, 12843319, 15517393, 17384219, 18673552, 18285823, 23919827, 25970827, 31511490). The variant alters the BMP9 response and reduces kinase activity in functional studies (PMID: 14684682, 20501893, 27869117). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Two missense changes involving the same residue (p.Arg374Gly, p.Arg374Trp), but a larger physicochemical change, have been reported as pathogenic in HHT individuals (ClinVar). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 374 of the ACVRL1 protein (p.Arg374Gln). 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: 12700602, 18285823, 21158752, 25970827). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411314). 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. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 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, 15517393, 17384219, 20501893). 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	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hereditary hemorrhagic telangiectasia type 2 (MIM#600376). Protein truncating variants are known to cause disease through a loss of function mechanism, while missense variants have been associated with both loss of function and dominant negative mechanisms (PMIDs: 26176610, 16470589, 16282348). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical expression is known to be extremely variable and age-dependent (PMID: 19767588). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated kinase domain (PMID: 20501893). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg374Trp) has been reported in multiple families with hereditary hemorrhagic telangiectasia (HHT) and it is believed to have resulted from a founder effect (ClinVar; PMID: 33919892). In addition, p.(Arg374Gly) has been reported in an individual with HHT (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with hereditary hemorrhagic telangiectasia and it is also believed to have resulted from a founder effect (ClinVar; PMID: 33919892). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutagenesis studies demonstrated that both p.(Arg374Gln) and p.(Arg374Trp) did not bind to the specific ligand BMP9 (PMID: 20501893). (SP) 1208 -Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 26, 2022	The ACVRL1 c.1121G>A; p.Arg374Gln variant (rs1060503248) has been reported in the literature in individuals with hereditary hemorrhagic telangiectasia (HHT) or pulmonary arterial hypertension (PAH) (Abdalla 2003, Harrison 2003, McDonald 2011, Yang 2018), and has been shown to have defective BMP9 ligand signaling (Ricard 2010). This variant has been reported in ClinVar (Variation ID: 411314) and is absent from the general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 374 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.654). Another amino acid substitution at this codon (p.Arg374Trp) has been reported in multiple individuals with HHT and is considered disease-causing (Harrison 2003, Nishida 2012). Based on available information, the p.Arg374Gln variant is considered to be pathogenic. REFERENCES Abdalla SA et al. Disease-associated mutations in conserved residues of ALK-1 kinase domain. Eur J Hum Genet. 2003 Apr;11(4):279-87. Harrison RE 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 Dec;40(12):865-71. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 ; 158A(11): 2829-2834. Ricard N et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010 Sep 2;116(9):1604-12. Yang H et al. Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients. Respir Res. 2018 May 9;19(1):87. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 12, 2024	PP1_strong, PM2, PM5, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ACVRL1: PS4, PM1, PM5, PP1, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2024	Published functional studies in transfected cultured cells suggest that although ACVRL1 receptors harboring R374Q can bind BMP9 ligand at the cell surface, the BMP9 signaling response is impaired (PMID: 20501893); Segregates with HHT in at least two affected relatives from two families (PMID: 12700602, 23919827); 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: 18673552, 17384219, 23919827, 18285823, 14684682, 15517393, 17786384, 25970827, 21158752, 29743074, 26387786, 31511490, 34872578, 12700602, 32300199, 33919892, 20501893) -

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

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2021

The p.R374Q pathogenic mutation (also known as c.1121G>A), located in coding exon 7 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1121. The arginine at codon 374 is replaced by glutamine, an amino acid with highly similar properties. This mutation was initially reported in in two possibly related hereditary hemorrhagic telangiectasia (HHT) families and was observed to segregate with disease in both families (Abdalla SA et al. Eur J Hum Genet, 2003 Apr;11:279-87). This mutation has been reported in additional individuals and families with HHT (Fontalba A et al. BMC Med. Genet., 2008 Aug;9:75; Chen YJ et al. Eur J Clin Invest, 2013 Oct;43:1016-24; McDonald J et al. Genet Med, 2020 07;22:1201-1205). The p.R374Q mutation is located in the intracellular kinase domain of the ALK1 protein, and in vitro 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). 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

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.;D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

-0.044

MutationAssessor

Uncertain

2.2

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.92

MutPred

0.95

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

MVP

0.93

MPC

1.7

ClinPred

1.0

GERP RS

5.0

Varity_R

0.95

gMVP

0.90

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