rs1085307429

Variant names:

• chr12-51920849-C-T
• rs1085307429
• NM_000020.3:c.1468C>T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_Supporting PS4 PVS1_Strong PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000020.3: c.1468C>T (p.Gln490Ter) variant in ACVRL1 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense medicated decay, however it is a truncation of a functionally important region (removes amino acids 490-503) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMID:15879500, 16829353, 20301525). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID:16829353, 16540754, 32573726, 11484689, Internal lab contributors). The variant has been reported to segregate with HHT in several affected family members from two large families (PP1_Strong; PMID:16829353, 11484689). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PS4, PP1_Strong (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA384906013/MONDO:0010880/135

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACVRL1 NM_000020.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 0.328

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.1468C>T	p.Gln490*	stop_gained	Exon 10 of 10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1468C>T	p.Gln490*	stop_gained	Exon 10 of 10	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:3

Jan 01, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1+PM2+PP4 -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln490*) in the ACVRL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the ACVRL1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ACVRL1-related conditions (PMID: 11484689, 16429404, 24603890). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 426040). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mar 15, 2024

ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000020.3: c.1468C>T (p.Gln490Ter) variant in ACVRL1 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense medicated decay, however it is a truncation of a functionally important region (removes amino acids 490-503) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 15879500, 16829353, 20301525). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID: 16829353, 16540754, 32573726, 11484689, Internal lab contributors). The variant has been reported to segregate with HHT in several affected family members from two large families (PP1_Strong; PMID: 16829353, 11484689). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PS4, PP1_Strong (specification version 1.0.0; 1/4/2024). -

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

- -

not provided Pathogenic:1

Feb 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM2_supporting, PS4, PVS1_moderate -

Hereditary factor VIII deficiency disease Pathogenic:1

Dec 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hemorrhagic telangiectasia Pathogenic:1

May 02, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in ACVRL1 is a nonsense variant that may cause a premature stop codon, p.(Gln490*), that is predicted to escape nonsense-mediated decay and remove <10% of the protein, however, it is a truncation of a functionally important region (removes amino acids 490-503) in a gene where loss-of-function is an established disease mechanism (PMID: 11062473, 8640225, 15879500). This variant is absent from the population database gnomAD v4.1. This variant has been reported in multiple individuals with a clinical diagnosis of hereditary haemorrhagic telangiectasia and cosegregates with the disease in multiple families (PMID: 11484689, 16429404, 16829353, 20056902, 25892364, 32573726). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Strong, PS4, PP1_Strong, PM2_Supporting. -

Cardiovascular phenotype Pathogenic:1

Dec 16, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q490* pathogenic mutation (also known as c.1468C>T), located in coding exon 9 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1468. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of theACVRL1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 2.8% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT), as well as in individuals with concerns for HHT (El-Harith et al. Eur J Med Genet 2006 Oct;49:323-30; Lenato GM et al. Hum Mutat, 2006 Feb;27:213-4; Olivieri C et al. Genet Med, 2006 Mar;8:183-90; T&oslash;rring PM et al. Clin Genet, 2014 Aug;86:123-33). Additionally, this alteration segregated with disease in one family (Trembath RC et al. N. Engl. J. Med., 2001 Aug;345:325-34). 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
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.68
GERP RS		3.4

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

Other links and lift over

dbSNP: rs1085307429; hg19: chr12-52314633;