rs863223412

chr12-51915438-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):c.986G>A(p.Arg329His) 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. 13/21 in silico tools predict a damaging 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:3
• 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 17 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000020.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ACVRL1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 12-51915438-G-A is Pathogenic according to our data. Variant chr12-51915438-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 212801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51915438-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.986G>A	p.Arg329His	missense_variant	7/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.986G>A	p.Arg329His	missense_variant	7/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 329 of the ACVRL1 protein (p.Arg329His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hemorrhagic telangiectasia (PMID: 12700602, 16123970, 32300199; Invitae). ClinVar contains an entry for this variant (Variation ID: 212801). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2015

p.Arg329His (R329H) CGC>CAC: c.986 G>A in exon 7 of the ACVRL1 gene (NM_000020.2). The R329H mutation in the ACVRL1 gene has been reported in at least two unrelated individuals with HHT (Abdalla S et al., 2003; Argyriou L et al., 2005). Furthermore, the R329H mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R329H results in a conservative amino acid substitution at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, mutations in nearby residues (H328Y, H328P, H328Q, D330Y, D330N, D330H) have been reported in association with HHT, further supporting the functional importance of this region of the protein. In summary, R329H in the ACVRL1 gene is interpreted as a disease-causing mutation. This variant was found in HHT-PANCARD -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2019

The p.R329H pathogenic mutation (also known as c.986G>A), located in coding exon 6 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 986. The arginine at codon 329 is replaced by histidine, an amino acid with highly similar properties. This mutation was described in an individual with telangiectasias and pulmonary and cerebral ateriovenous malformations (AVMs) (Abdalla SA et al. Eur. J. Hum. Genet., 2003 Apr;11:279-87). It was also reported in an individual with hereditary hemorrhagic telangiectasia who underwent liver transplantation (Argyriou L et al. Liver Transpl., 2005 Sep;11:1132-5). 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	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.99		Loss of MoRF binding (P = 0.0734);.;.;
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.97

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: rs863223412; hg19: chr12-52309222;