rs1555152520

Positions:

• chr12-51913302-T-C
• chr12-51913302-T-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.265T>C​(p.Cys89Arg) variant causes a missense 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C89F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.75

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 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000020.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-51913302-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 533352.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ACVRL1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 12-51913302-T-C is Pathogenic according to our data. Variant chr12-51913302-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.265T>C	p.Cys89Arg	missense_variant	3/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.265T>C	p.Cys89Arg	missense_variant	3/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 16, 2016

- -

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2021

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. This variant has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 439381). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 89 of the ACVRL1 protein (p.Cys89Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant affects a cysteine residue located within the ACVRL1 protein ectodomain. Cysteine residues in this domain of ACVRL1 are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 22028876, 22718755, 22799562). In addition, missense substitutions within the ACVRL1 ectodomain affecting cysteine residues are overrepresented in patients with HHT (PMID: 20501893, 26176610 and www.hhtmutation.org). This variant disrupts the p.Cys89 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The p.C89R variant (also known as c.265T>C), located in coding exon 2 of the ACVRL1 gene, results from a T to C substitution at nucleotide position 265. The cysteine at codon 89 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT), as well as in individuals with concerns for HHT (McDonald J et al. Genet Med, 2020 07;22:1201-1205; Major T et al. J Clin Med, 2021 Aug;10:[ePub ahead of print]; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-9.6	D;D;D;D
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;T;D
Polyphen		1.0	.;D;.;.
Vest4		0.63, 0.61
MutPred		0.96		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		1.0

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: rs1555152520; hg19: chr12-52307086;