NM_000020.3(ACVRL1):c.200G>A (p.Arg67Gln) AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV000534448.9

Allele description [Variation Report for NM_000020.3(ACVRL1):c.200G>A (p.Arg67Gln)]

NM_000020.3(ACVRL1):c.200G>A (p.Arg67Gln)

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.200G>A (p.Arg67Gln)

Other names:

p.R67Q:CGG>CAG

HGVS:

NC_000012.12:g.51913237G>A
NG_009549.1:g.10820G>A
NM_000020.3:c.200G>AMANE SELECT
NM_001077401.2:c.200G>A
NP_000011.2:p.Arg67Gln
NP_000011.2:p.Arg67Gln
NP_001070869.1:p.Arg67Gln
LRG_543t1:c.200G>A
LRG_543:g.10820G>A
LRG_543p1:p.Arg67Gln
NC_000012.11:g.52307021G>A
NM_000020.2:c.200G>A
P37023:p.Arg67Gln

Protein change:

R67Q

Links:

UniProtKB: P37023#VAR_006206; dbSNP: rs863223414

NCBI 1000 Genomes Browser:

rs863223414

Molecular consequence:

NM_000020.3:c.200G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001077401.2:c.200G>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
SCV000639398	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 9245985, 15880681, 16706966, 18498373, 23722869, 10187774, 14684682, 17786384, 18285823, 22377182, 22553411, 28492532
SCV001439409	NIHR Bioresource Rare Diseases, University of Cambridge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2018)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 32573726, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000639398

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV001439409

NIHR Bioresource Rare Diseases, University of Cambridge

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 1, 2018)

unknown

research

PubMed (2)
[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	unknown	yes	2	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.

Berg JN, Gallione CJ, Stenzel TT, Johnson DW, Allen WP, Schwartz CE, Jackson CE, Porteous ME, Marchuk DA.

Am J Hum Genet. 1997 Jul;61(1):60-7.

PubMed [citation]

PMID:: 9245985
PMCID:: PMC1715857

High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients.

Schulte C, Geisthoff U, Lux A, Kupka S, Zenner HP, Blin N, Pfister M.

Hum Mutat. 2005 Jun;25(6):595.

PubMed [citation]

PMID:: 15880681

See all PubMed Citations (14)

Details of each submission

From Invitae, SCV000639398.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 67 of the ACVRL1 protein (p.Arg67Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemorrhagic telangiectasia (PMID: 9245985, 15880681, 16706966, 17786384, 18498373, 23722869). ClinVar contains an entry for this variant (Variation ID: 212803). 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 80%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 10187774, 14684682). This variant disrupts the p.Arg67 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17786384, 18285823, 22377182, 22553411). 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.

#	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 NIHR Bioresource Rare Diseases, University of Cambridge, SCV001439409.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	research	PubMed (2)

Description

PM2+PP4+PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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