rs1057517944

Positions:

• chr12-51920816-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1435C>T​(p.Arg479Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,804 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 (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACVRL1 NM_000020.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.537

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-51920816-C-T is Pathogenic according to our data. Variant chr12-51920816-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 372722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51920816-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.1435C>T	p.Arg479Ter	stop_gained	10/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1435C>T	p.Arg479Ter	stop_gained	10/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251420 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461804 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:5

Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PVS1+PM2+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	This sequence change creates a premature translational stop signal (p.Arg479*) in the ACVRL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the ACVRL1 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 15024723, 15065824, 15517393, 15712271, 16429404, 16540754, 18673552, 21158752, 23722869). ClinVar contains an entry for this variant (Variation ID: 372722). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg479 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16470787, 16705692, 20501893, 21158752). 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 29, 2023	The ACVRL1 c.1435C>T; p.Arg479Ter variant (rs1057517944) is reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (HHT; Abdalla 2004 and 2005, Canzonieri 2014, Chen 2013, Fontalba 2008, Gedge 2007, Komiyama 2014, Lenato 2006, Lesca 2004, Letterboer 2005, Olivieri 2006, Yan 2006). This variant is reported in ClinVar (Variation ID: 372722), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the ACVRL1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein, and functional analyses of the variant protein demonstrate a loss of ligand-induced receptor signaling and down-regulation of the protein (Garamszeg 2001). Additionally, another downstream truncating variant, c.1468C>T; p.Gln490Ter, has been reported in multiple patients with HHT (Girerd 2010, Machado 2015, Trembath 2001) and is considered pathogenic. Based on available information, the c.1435C>T; p.Arg479Ter variant is considered to be pathogenic. REFERENCES Abdalla SA et al. Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia. Eur Respir J. 2004 Mar;23(3):373-7. PMID: 15065824. Abdalla SA et al. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat. 2005 Mar;25(3):320-1. PMID: 15712271. Canzonieri C et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genet Med. 2014 Jan;16(1):3-10. PMID: 23722869. Chen YJ et al. Clinical and genetic characteristics of Chinese patients with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension. Eur J Clin Invest. 2013 Oct;43(10):1016-24. PMID: 23919827. Fontalba A et al. Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2008 Aug 1;9:75. PMID: 18673552. Garamszegi N et al. Transforming growth factor beta receptor signaling and endocytosis are linked through a COOH terminal activation motif in the type I receptor. Mol Biol Cell. 2001 Sep;12(9):2881-93. PMID: 11553725. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. PMID: 17384219. Girerd B et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010 Apr 15;181(8):851-61. PMID: 20056902. Komiyama M et al. Hereditary hemorrhagic telangiectasia in Japanese patients. J Hum Genet. 2014 Jan;59(1):37-41. PMID: 24196379. 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. PMID: 16429404. 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. PMID: 15024723. Letterboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. PMID: 15517393. Machado RD et al. Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat. 2015 Dec;36(12):1113-27. PMID: 26387786. Olivieri C et al. Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia. Genet Med. 2006 Mar;8(3):183-90. PMID: 16540754. Trembath RC et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001 Aug 2;345(5):325-34. PMID: 11484689. Yan ZM et al. A novel mutation in ALK-1 causes hereditary hemorrhagic telangiectasia type 2. J Dent Res. 2006 Aug;85(8):705-10. PMID: 16861286. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 haemorrhagic telangiectasia type 2 (MIM#600376) (PMID: 16282348, PMID: 26176610). (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 extremely variable and age-dependent (PMID: 19767588). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote). (SP) 0702 - Truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Other protein truncating variants have previously been reported as pathogenic in individuals with hereditary haemorrhagic telangiectasia type 2 (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals.This variant has previously been reported in individuals with hereditary haemorrhagic telangiectasia (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2022	Nonsense variant in the C-terminus predicted to result in protein truncation as the last 25 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21158752, 16429404, 26387786, 23722869, 15024723, 17384219, 16540754, 24196379, 16861286, 18673552, 15517393, 15065824, 15712271, 15266205, 17786384, 23919827, 29631995, 30578397, 31220907, 32503579, 32300199) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2022	PP1_strong, PM2_supporting, PS4, PVS1_moderate -

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

-

- -

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genetics, Medical University of Vienna

-

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2019

The p.R479* pathogenic mutation (also known as c.1435C>T) is located in coding exon 9 of the ACVRL1 gene. This changes the amino acid from an arginine to a stop codon within coding exon 9. This stop codon occurs at the 3' terminus of ACVRL1, impacts the last twenty-five amino acids of the protein, and may not trigger nonsense-mediated mRNA decay. This mutation has been detected in multiple individuals from hereditary hemorrhagic telangiectasia (HHT) cohorts (Lesca et al. Hum Mutat. 2004;23:289-299; Gedge F et al. J Mol Diagn. 2007 Apr;9(2):258-65; Canzonieri C et al. Genet Med. 2014 Jan;16(1):3-10; Komiyama M et al. J Hum Genet. 2014 Jan;59(1):37-41). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jul 07, 2023

This sequence change in ACVRL1 is a nonsense variant predicted to cause a premature stop codon, p.(Arg479*), in biologically relevant exon 10/10, 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 25 amino acids) in a gene where loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.003% (1/34,588 alleles) in the Latino/Admixed American population. This variant has been reported in multiple individuals with a clinical diagnosis of hereditary haemorrhagic telangiectasia, and segregates with disease in multiple families (PMID: 15024723, 16540754, 15065824, 16861286). 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, PM2_Supporting, PP1_Strong, PS4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.53	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.84
GERP RS		4.4

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: rs1057517944; hg19: chr12-52314600;