rs28936688

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_000020.3(ACVRL1):c.1031G>A(p.Cys344Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ACVRL1
NM_000020.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.99

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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, 0.993

PP5

Variant 12-51915483-G-A is Pathogenic according to our data. Variant chr12-51915483-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8254.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 link	c.1031G>A	p.Cys344Tyr	missense_variant	Exon 7 of 10	ENST00000388922.9	NP_000011.2	P37023A0A0S2Z310

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9 link	c.1031G>A	p.Cys344Tyr	missense_variant	Exon 7 of 10	1	NM_000020.3	ENSP00000373574.4		P37023

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456042

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723364

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2

Pathogenic:5

Jun 12, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACVRL1 c.1031G>A; p.Cys344Tyr variant (rs28936688) has been reported in several individuals with HHT (Abdalla 2000, Bayrak-Toydemir 2004, Gedge 2007, Harrison 2003, Schulte 2005, Wehner 2006). This variant is also reported in ClinVar (Variation ID: 8254). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is pathogenic (REVEL: 0.929). Based on available information, this variant is considered to be pathogenic. References: Abdalla SA et al. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Hum Mol Genet. 2000 May 1;9(8):1227-37. PMID: 10767348. Bayrak-Toydemir P et al. Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. Genet Med. 2004 Jul-Aug;6(4):175-91. PMID: 15266205. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. PMID: 17384219. Harrison RE et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003 Dec;40(12):865-71. PMID: 14684682. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595. PMID: 15880681. Wehner LE et al. Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations. Clin Genet. 2006 Mar;69(3):239-45. PMID: 16542389. -

Dec 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 23, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous missense variant c.1031G>A (p.Cys344Tyr) identified in the ACVRL1 gene is a well-known pathogenic variant that has been reported in multiple unrelated individuals and families affected with HHT2 [PMID: 10767348, 14684682, 15880681, 16540754, 16542389, 17384219, 12114496]. The variant is absent from the gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. The variant has been reported as Pathogenic in the ClinVar database by multiple independent laboratories (Variation ID: 8254). This variant affects a highly conserved residue (Cys344)located in the protein kinase domain of ACVRL1 and is predicted deleterious by multiple in silico prediction tools (CADD score = 34.0, REVEL score = 0.929). In vitro functional studies have shown that the p.Cys344Tyr variant results in abnormal ACVRL1 trafficking [PMID: 14684682, 16282348]. Based on the available evidence, the heterozygous c.1031G>A (p.Cys344Tyr) variant identified in the ACVRL1 gene is reported as Pathogenic. -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation has been described in the literature as disease-causing and has been identified once in our laboratory in an individual with HHT; the affected parent was unavailable for testing. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 344 of the ACVRL1 protein (p.Cys344Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 10767348, 12114496, 14684682, 15880681, 16540754, 16542389, 17384219). ClinVar contains an entry for this variant (Variation ID: 8254). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACVRL1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 14684682, 16282348). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

May 21, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated that p.(C344Y) imparts a dominant-negative effect by suppressing the activity of wild-type ACVRL1 (PMID: 16282348); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Different missense changes at this residue (p.(C344R) and p.(C344F)) have been reported in association with a ACVRL1-related phenotype in the published literature (PMID: 23124896, 12114496); This variant is associated with the following publications: (PMID: 14684682, 16470787, 17384219, 16542389, 17786384, 25970827, 15880681, 10767348, 12114496, 16540754, 29631995, 32503579, 32300199, 23124896, 16282348) -

Jun 13, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_moderate, PP3, PM1, PM2_supporting, PM5, PS3, PS4 -

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia

Pathogenic:1

Dec 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

See cases

Pathogenic:1

Jun 08, 2020

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys344Tyr substitutes the cysteine with tyrosine at position 344 of the protein. This variant has previously been reported as pathogenic in a clinically affected individual with HHT (PMID: 10767348; see patient H167). This variant has also been reported in two individuals with adult-onset pulmonary arterial hypertension (PAH); one with PAH related to HHT (PMID: 29631995; see patient FPPH110 and FPPH139-01). Further supporting pathogenicity, different missense changes at the same amino acid residue (p.Cys344Arg, p.Cys344Phe) have been reported as pathogenic (PMID: 19767588, PMID: 12114496 and others). The p.Cys344Tyr has not been documented in large population cohorts (0 of 246,970 alleles; Genome Aggregation Database v2.1). This is an evolutionary conserved amino acid and in silico tools predict this variant has a damaging effect. -

Cardiovascular phenotype

Pathogenic:1

Oct 01, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C344Y pathogenic mutation (also known as c.1031G>A), located in coding exon 6 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1031. The cysteine at codon 344 is replaced by tyrosine, an amino acid with highly dissimilar properties. This pathogenic mutation has been identified in multiple unrelated patients with hereditary hemorrhagic telangiectasia (Abdalla SA et al. Hum. Mol. Genet., 2000 May;9:1227-37; Harrison RE et al. J. Med. Genet., 2003 Dec;40:865-71; Schulte C et al. Hum. Mutat., 2005 Jun;25:595; Wehner LE et al. Clin. Genet., 2006 Mar;69:239-45; Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65; Richards-Yutz J et al. Hum. Genet., 2010 Jul;128:61-77). ln vitro functional studies demonstrated this mutation had a dominant-negative effect on the normal protein and had reduced protein expression on the cell surface (Gu Y et al. Blood, 2006 Mar;107:1951-4). 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 BayesDel 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

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

M;.;.

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-11

D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.95

MutPred

0.96

Gain of methylation at K339 (P = 0.1167);.;.;

MVP

1.0

MPC

2.0

ClinPred

1.0

GERP RS

5.1

Varity_R

1.0

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over