12-51915483-G-T

Variant names:

• chr12-51915483-G-T
• rs28936688
• NM_000020.3:c.1031G>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1031G>T​(p.Cys344Phe) variant causes a missense change involving the alteration of a 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: 33)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.99

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ACVRL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 203 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.4458 (below the threshold of 3.09). Trascript score misZ: 3.182 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 12-51915483-G-T is Pathogenic according to our data. Variant chr12-51915483-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 658228.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.1031G>T	p.Cys344Phe	missense_variant	Exon 7 of 10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1031G>T	p.Cys344Phe	missense_variant	Exon 7 of 10	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1

Nov 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with ACVRL1-related conditions (PMID: 12114496, 30578397; Invitae). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 344 of the ACVRL1 protein (p.Cys344Phe). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 658228). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 23124896). This variant disrupts the p.Cys344 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16470787, 16752392, 18673552, 19767588). 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. -

Cardiovascular phenotype Pathogenic:1

Oct 25, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C344F pathogenic mutation (also known as c.1031G>T), located in coding exon 6 of the ACVRL1 gene, results from a G to T substitution at nucleotide position 1031. The cysteine at codon 344 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was detected in cohorts reported to meet diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT), individuals who were suspected of having HHT, and individuals submitted for HHT genetic testing (Olivieri C, J. Med. Genet. 2002 Jul; 39(7):E39; Olivieri C et al. J Hum Genet. 2007 Sep;52(10):820-829; Invitae pers. comm.). This variant has also been detected in a pulmonary arterial hypertension case (Wang XJ et al. Eur Respir J. 2019 03;53(3)). Other alterations at the same codon, p.C344Y (c.1031G>A) and p.C344R (c.1030T>C), have been also reported in association with HHT (Abdalla SA et al. Hum. Mol. Genet., 2000 May;9:1227-37; Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75). An in vitro study demonstrated that this mutation interferes with transport of the protein to the cell surface (Hume AN, Mol. Cell. Biochem. 2013 Jan; 373(1-2):247-57). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. 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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0040	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.94
MutPred		0.95		Loss of methylation at K339 (P = 0.1881);.;.;
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.1
Varity_R		1.0
gMVP		0.95

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: rs28936688; hg19: chr12-52309267;