NM_000020.3(ACVRL1):c.1436G>A (p.Arg479Gln) AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 27, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000546029.20

Allele description [Variation Report for NM_000020.3(ACVRL1):c.1436G>A (p.Arg479Gln)]

NM_000020.3(ACVRL1):c.1436G>A (p.Arg479Gln)

Gene:

ACVRL1:activin A receptor like type 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.13

Genomic location:

Preferred name:

NM_000020.3(ACVRL1):c.1436G>A (p.Arg479Gln)

HGVS:

NC_000012.12:g.51920817G>A
NG_009549.1:g.18400G>A
NM_000020.3:c.1436G>AMANE SELECT
NM_001077401.2:c.1436G>A
NP_000011.2:p.Arg479Gln
NP_000011.2:p.Arg479Gln
NP_001070869.1:p.Arg479Gln
LRG_543t1:c.1436G>A
LRG_543:g.18400G>A
LRG_543p1:p.Arg479Gln
NC_000012.11:g.52314601G>A
NM_000020.2:c.1436G>A

Protein change:

R479Q

Links:

dbSNP: rs1085307426

NCBI 1000 Genomes Browser:

rs1085307426

Molecular consequence:

NM_000020.3:c.1436G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001077401.2:c.1436G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Telangiectasia, hereditary hemorrhagic, type 2 (HHT2)
Synonyms:: Telangiectasia, hereditary hemorrhagic, type II; Osler Weber Rendu syndrome type 2
Identifiers:: MONDO: MONDO:0010880; MedGen: C1838163; Orphanet: 774; OMIM: 600376

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000602430	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Dec 17, 2018)	germline	clinical testing	Citation Link,
SCV000639396	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16470787, 16705692, 21158752, 20501893, 28492532
SCV004175420	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 9, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16705692, 20501893, 32300199, 34872578, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000602430

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Dec 17, 2018)

germline

clinical testing

Citation Link,

SCV000639396

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 27, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004175420

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 9, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.

Bayrak-Toydemir P, McDonald J, Markewitz B, Lewin S, Miller F, Chou LS, Gedge F, Tang W, Coon H, Mao R.

Am J Med Genet A. 2006 Mar 1;140(5):463-70.

PubMed [citation]

PMID:: 16470787

Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis.

McDonald J, Damjanovich K, Millson A, Wooderchak W, Chibuk JM, Stevenson DA, Gedge F, Bayrak-Toydemir P.

Clin Genet. 2011 Apr;79(4):335-44. doi: 10.1111/j.1399-0004.2010.01596.x. Epub 2010 Dec 16.

PubMed [citation]

PMID:: 21158752

See all PubMed Citations (8)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000602430.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ACVRL1 c.1436G>A;p.Arg479Gln variant has been described in families and individuals with hereditary hemorrhagic telangiectasia (HHT) or pulmonary arterial hypertension (PAH) and has been described as segregating with disease (Bayrak-Toydemir 2006, Bayrak-Toydemir 2008, Fujiwara 2008, Gedge 2007, Lesca 2006, McDonald 2011). It is reported as pathogenic in ClinVar (Variation ID: 426035) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 479 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant is deleterious. Additionally, this variant has been shown to have reduced function (Ricard 2010). Based on available information, this variant is considered pathogenic. REFERENCES Bayrak-Toydemir P et al. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A. 2006 Mar 1;140(5):463-70. Bayrak-Toydemir P et al. Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model. Exp Mol Pathol. 2008 Aug;85(1):45-9.. Fujiwara M et al. Implications of mutations of activin receptor-like kinase 1 gene (ALK1) in addition to bone morphogenetic protein receptor II gene (BMPR2) in children with pulmonary arterial hypertension. Circ J. 2008 Jan;72(1):127-33. 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. Lesca G et al. Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat. 2006 Jun;27(6):598. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. Ricard N et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010 Sep 2;116(9):1604-12.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000639396.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 479 of the ACVRL1 protein (p.Arg479Gln). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with hemorrhagic telangiectasia (PMID: 16470787, 16705692, 21158752; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 426035). 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%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 20501893). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV004175420.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The ACVRL1 c.1436G>A variant is classified as Likely Pathogenic (PS4_Moderate, PM2_supporting, PS3_supporting, PM1_supporting, PP3). The ACVRL1 c.1436G>A variant is a single nucleotide change in exon 10/10 of the ACVRL1 gene, which is predicted to change the amino acid arginine at position 479 in the protein to glutamine. The variant has been reported in multiple individuals with a clinical presentation of HHT (PMID:34872578, PMID:32300199, PMID:16705692) (PS4_Moderate). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 151854 sequenced alleles; highest frequency = 0.0029%, Non-Finnish European population) (PM2_supporting). Functional studies show a deleterious effect of this variant (PMID:20501893) (PS3_supporting). This variant is located in the conserved serine/threonine kinase domain (PMID:34872578) (PM1_supporting). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs1085307426) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 426035). It has not been reported in HGMD.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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