rs1085307422

Positions:

• chr12-51920766-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1385C>G​(p.Ser462*) variant causes a stop gained change. 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:4
• Conservation: PhyloP100: 4.97

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 14 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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-51920766-C-G is Pathogenic according to our data. Variant chr12-51920766-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 426031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.1385C>G	p.Ser462*	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.1385C>G	p.Ser462*	stop_gained	10/10	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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change creates a premature translational stop signal (p.Ser462*) in the ACVRL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 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 individuals with ACVRL1-related conditions (PMID: 15065824, 29631995; Invitae). ClinVar contains an entry for this variant (Variation ID: 426031). This variant disrupts a region of the ACVRL1 protein in which other variant(s) (p.Gln490*) have been determined to be pathogenic (PMID: 11484689, 16429404, 24603890). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 03, 2018

The ACVRL1 c.1385C>G; p.Ser462Ter variant (rs1085307422) is reported in the literature in individuals with HHT (Abdalla 2004, Olivieri 2007) and is reported in ClinVar (Variation ID: 426031). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein. Furthermore, several truncating variants downstream (p.Leu464Ter, p.Glu470Ter, p.Cys471Ter, p.Arg479Ter, p.Gln490Ter) have been associated with HHT and are considered pathogenic (see HHT database link). Based on available information, the p.Ser462Ter variant is considered pathogenic. REFERENCES Link to ACVRL1 HHT database: http://arup.utah.edu/database/ACVRL1/ACVRL1_display.php Abdalla SA et al. Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia. Eur Respir J. 2004 Mar;23(3):373-7. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52(10):820-9. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2017

The p.S462* pathogenic mutation (also known as c.1385C>G), located in coding exon 9 of the ACVRL1 gene, results from a C to G substitution at nucleotide position 1385. This changes the amino acid from a serine to a stop codon within coding exon 9. This mutation was first reported in a proband with pulmonary hypertension, epistaxis, telangiectasia, pulmonary, hepatic, and gastrointestinal AVMs, and a family history of hereditary hemorrhagic telangiectasia (HHT); the mutation co-segregated with disease in the family (Abdalla SA et al. Eur. Respir. J., 2004 Mar;23:373-7). This mutation was subsequently reported in an individual with a definite diagnosis of HHT based on Curacao criteria (Olivieri C et al. J. Hum. Genet., 2007 Sep;52:820-9). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.93
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1085307422; hg19: chr12-52314550; COSMIC: COSV66359525; COSMIC: COSV66359525;