rs1085307429

Positions:

• chr12-51920849-C-T

Variant summary

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

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 ENST00000388922.9 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• 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/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.1468C>T	p.Gln490Ter	stop_gained	10/10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1468C>T	p.Gln490Ter	stop_gained	10/10	1	NM_000020.3	ENSP00000373574	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PVS1+PM2+PP4 -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	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

Pathogenic, no assertion criteria provided

literature only

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

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 28, 2023

PP1_strong, PM2_supporting, PS4, PVS1_moderate -

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 17, 2024

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2021

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; Tørring 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
MutationTaster	Benign	1.0	D;D;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;