rs1131691686

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000020.3(ACVRL1):c.1135G>A(p.Glu379Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,612 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. E379G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACVRL1
NM_000020.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.99

Publications

9 publications found

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 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

ACVRL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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 chr12-51916123-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2748456.Status of the report is criteria_provided_single_submitter, 1 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, 0.996

PP5

Variant 12-51916122-G-A is Pathogenic according to our data. Variant chr12-51916122-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 429940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3 link	c.1135G>A	p.Glu379Lys	missense_variant	Exon 8 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.1135G>A	p.Glu379Lys	missense_variant	Exon 8 of 10	1	NM_000020.3	ENSP00000373574.4		P37023

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251236

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111806

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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

Jun 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ACVRL1 c.1135G>A; p.Glu379Lys variant (rs1131691686) has been reported in multiple unrelated individuals diagnosed with hereditary hemorrhagic telangiectasia (Brakensiek 2008, Fontalba 2008, Kuehl 2005, Lenato 2006, Lesca 2004, Nishida 2012). In functional assays, this variant exhibits a decreased BMP9 response and inability to properly localize to the cell surface (Alaa El Din 2015). This variant is reported in the ClinVar database (Variation ID: 429940), and it is found on only two chromosomes (2/251236 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 379 is a highly conserved residue in the protein kinase domain, computational analyses predict that this variant is deleterious (REVEL: 0.969). Based on the above information, this variant is considered pathogenic. References: Alaa El Din F et al. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. PLoS One. 2015 Jul 15;10(7):e0132111. Brakensiek K et al. Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2008 Aug;74(2):171-7. Fontalba A et al. Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2008 Aug 1;9:75. Kuehl HK et al. Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations. Hum Mutat. 2005 Mar;25(3):320. 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. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 379 of the ACVRL1 protein (p.Glu379Lys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 15024723, 15712270, 16429404, 18498373, 22991266, 24603890). ClinVar contains an entry for this variant (Variation ID: 429940). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 26176610). For these reasons, this variant has been classified as Pathogenic. -

Jul 18, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Mar 17, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest that p.(E379K) has a negative impact on ACVRL1 receptor activity and protein maturation (PMID: 26176610); 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: 18498373, 15879500, 15266205, 22991266, 18673552, 17384219, 15712270, 15521985, 15024723, 26176610, 30578397, 32503579, 32300199, 16429404, 23535011, 34966542, 24603890) -

Jun 22, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM2_supporting, PS3, PS4 -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary hemorrhagic telangiectasia

Pathogenic:1

Apr 12, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu379Lys variant in ACVRL1 has been reported in >5 individuals with hereditary hemorrhagic telangiectasia (HHT; Lesca 2004 PMID: 15024723, Kuehl 2005 PMID: 15712270, Lenato 2006 PMID: 16429404). It has also been identified in 0.001% (1/69794) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 429940). Computational prediction tools and conservation analyses support that this variant may impact the protein. In vitro functional studies provide some evidence that this variant impacts protein function (Alaa El Din 2015 PMID: 26176610); however, these types of assays may not accurately represent biological function. Additionally, the number of ACVRL1 missense variants in the general population is lower than expected (Z=3.18, https://gnomad.broadinstitute.org/gene/ENSG00000139567), providing some evidence that this variant may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HHT. ACMG/AMP Criteria applied: PS4, PP2, PP3, PM2_supporting, PS3_supporting. -

Cardiovascular phenotype

Pathogenic:1

Jan 16, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E379K pathogenic mutation (also known as c.1135G>A), located in coding exon 7 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1135. The glutamic acid at codon 379 is replaced by lysine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension, and segregated with disease in at least one family (Lesca G et al. Hum. Mutat., 2004 Apr;23:289-99; Lenato GM et al. Hum. Mutat., 2006 Feb;27:213-4; Wang XJ et al. Eur Respir J, 2019 03;53; Zhao Y et al. Mol Genet Genomic Med, 2019 09;7:e893). In an assay testing ACVRL1 function, this variant showed a functionally abnormal result (Alaa El Din F et al. PLoS ONE, 2015 Jul;10:e0132111). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

0.52

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

1.0

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.5

H;.;.

PhyloP100

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.99

MutPred

0.97

Gain of methylation at E379 (P = 0.0068);.;.;

MVP

0.99

MPC

1.6

ClinPred

1.0

GERP RS

5.0

Varity_R

0.99

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over