rs1301762186

Variant names:

• chr12-51920794-C-A
• rs1301762186
• NM_000020.3:c.1413C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-51920794-C-A
• chr12-51920794-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1413C>A​(p.Cys471*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACVRL1 NM_000020.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.76
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 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 39 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-51920794-C-A is Pathogenic according to our data. Variant chr12-51920794-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 464759.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	c.1413C>A	p.Cys471*	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.1413C>A	p.Cys471*	stop_gained	Exon 10 of 10	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:2

Mar 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACVRL1 c.1413C>A; p.Cys471Ter variant (rs1301762186; ClinVar Variation ID: 464759) is reported in the literature in individuals affected with HHT (Bossler 2006, Kuchtey 2015, Nishida 2012). This variant is absent from the Genome Aggregation Database (v2.1.1), 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 ACVRL1 protein. Based on available information, this variant is considered to be pathogenic. References: Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 Jul;27(7):667-75. PMID: 16752392. Kuchtey RW et al. Severe open angle glaucoma in hereditary hemorrhagic telangiectasia. Clin Case Rep. 2015 Sep;3(9):725-7. PMID: 26401274. 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. PMID: 22991266. -

Feb 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a premature translational stop signal in the ACVRL1 gene (p.Cys471*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acids of the ACVRL1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 16752392, 22991266, 26401274). ClinVar contains an entry for this variant (Variation ID: 464759). This variant disrupts the C-terminus of the ACVRL1 protein. Other variant(s) that disrupt this region (p.Arg479*) have been determined to be pathogenic (PMID: 15024723, 16540754, 23722869). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jan 09, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C471* pathogenic mutation (also known as c.1413C>A), located in coding exon 9 of the ACVRL1 gene, results from a C to A substitution at nucleotide position 1413. This changes the amino acid from a cysteine to a stop codon within coding exon 9. This mutation was detected in multiple individual with clinical features of hereditary hemorrhagic telangiectasia (HHT), including one individual with epistaxis, telangiectasias, arteriovenous malformations, and a family history of HHT (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75; Nishida T et al. Am. J. Med. Genet. A, 2012 Nov;158A:2829-34; Kuchtey RW et al. Clin Case Rep, 2015 Sep;3:725-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		1.8
Vest4		0.88
GERP RS		4.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1301762186; hg19: chr12-52314578;