ClinVar Genomic variation as it relates to human health
NM_000020.3(ACVRL1):c.200G>A (p.Arg67Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000020.3(ACVRL1):c.200G>A (p.Arg67Gln)
Variation ID: 212803 Accession: VCV000212803.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.13 12: 51913237 (GRCh38) [ NCBI UCSC ] 12: 52307021 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 11, 2015 Feb 14, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000020.3:c.200G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000011.2:p.Arg67Gln missense NM_001077401.2:c.200G>A NP_001070869.1:p.Arg67Gln missense NC_000012.12:g.51913237G>A NC_000012.11:g.52307021G>A NG_009549.1:g.10820G>A LRG_543:g.10820G>A LRG_543t1:c.200G>A LRG_543p1:p.Arg67Gln P37023:p.Arg67Gln - Protein change
- R67Q
- Other names
- p.R67Q:CGG>CAG
- Canonical SPDI
- NC_000012.12:51913236:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ACVRL1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
985 | 996 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 31, 2023 | RCV000200439.16 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000534448.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2021 | RCV002415829.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883351.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
The ACVRL1 c.200G>A; p.Arg67Gln variant (rs863223414) has been reported in multiple unrelated individuals and families with hereditary hemorrhagic telangiectasia (Berg 1997, Canzonieri 2014, Giordano 2006, … (more)
The ACVRL1 c.200G>A; p.Arg67Gln variant (rs863223414) has been reported in multiple unrelated individuals and families with hereditary hemorrhagic telangiectasia (Berg 1997, Canzonieri 2014, Giordano 2006, Lenato 2006, Olivieri 2007, Schulte 2005). This variant is reported in the ClinVar database (Variation ID: 212803), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The arginine at codon 67 is highly conserved, and computational algorithms (SIFT, MutationTaster, Align GVGD) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg67Gln: https://www.ncbi.nlm.nih.gov/clinvar/variation/212803/ Berg JN et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997 Jul;61(1):60-7. Canzonieri C et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genet Med. 2014 Jan;16(1):3-10. Giordano P et al. Screening for children from families with Rendu-Osler-Weber disease: from geneticist to clinician. J Thromb Haemost. 2006 Jun;4(6):1237-45. Lenato GM et al. DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. Hum Mutat. 2006 Feb;27(2):213-4. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52(10):820-9. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595. (less)
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Likely pathogenic
(Jan 01, 2018)
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criteria provided, single submitter
Method: research
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Telangiectasia, hereditary hemorrhagic, type 2
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001439409.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
Comment:
PM2+PP4+PP5
Number of individuals with the variant: 2
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Pathogenic
(Nov 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000249633.14
First in ClinVar: Oct 11, 2015 Last updated: Dec 03, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate complete loss of signaling (Lux et al., 1999); In silico analysis … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate complete loss of signaling (Lux et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22028876, 14684682, 9245985, 23722869, 15880681, 22553411, 31400083, 11484689, 16706966, 16429404, 27860447, 17786384, 18498373, 32503579, 32573726, 35628811, 10187774) (less)
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Pathogenic
(Mar 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713595.3
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
PP1, PP4, PM2_supporting, PM5, PS3, PS4
Number of individuals with the variant: 5
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Telangiectasia, hereditary hemorrhagic, type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000639398.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Dec 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002722871.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R67Q pathogenic mutation (also known as c.200G>A), located in coding exon 2 of the ACVRL1 gene, results from a G to A substitution at … (more)
The p.R67Q pathogenic mutation (also known as c.200G>A), located in coding exon 2 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 200. The arginine at codon 67 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been identified in multiple unrelated individuals with hereditary hemorrhagic telangiectasia (Lenato GM et al. Hum. Mutat., 2006 Feb;27:213-4; Giordano P et al. J. Thromb. Haemost., 2006 Jun;4:1237-45; Olivieri C et al. J. Hum. Genet., 2007 Sep;52:820-9; Zhao Y et al. Mol Genet Genomic Med. 2019 09;7(9):e893). An in vitro functional study demonstrated that this mutation abolished protein signaling (Lux A et al. J. Biol. Chem., 1999 Apr;274:9984-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Distribution of Cerebrovascular Phenotypes According to Variants of the ENG and ACVRL1 Genes in Subjects with Hereditary Hemorrhagic Telangiectasia. | Gaetani E | Journal of clinical medicine | 2022 | PMID: 35628811 |
Founder Effects in Hereditary Hemorrhagic Telangiectasia. | Major T | Journal of clinical medicine | 2021 | PMID: 33919892 |
Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. | Shovlin CL | Blood | 2020 | PMID: 32573726 |
Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry. | Sánchez-Martínez R | Orphanet journal of rare diseases | 2020 | PMID: 32503579 |
PI3K (Phosphatidylinositol 3-Kinase) Activation and Endothelial Cell Proliferation in Patients with Hemorrhagic Hereditary Telangiectasia Type 1. | Iriarte A | Cells | 2019 | PMID: 31450639 |
Variant analysis in Chinese families with hereditary hemorrhagic telangiectasia. | Zhao Y | Molecular genetics & genomic medicine | 2019 | PMID: 31400083 |
Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. | Canzonieri C | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 23722869 |
Gastric angiodysplasia in a hereditary hemorrhagic telangiectasia type 2 patient. | Ha M | World journal of gastroenterology | 2012 | PMID: 22553411 |
A rare cause of fatal right ventricular cardiac decompensation. | Samol A | Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology | 2012 | PMID: 22377182 |
Mutation analysis of "Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique. | Sadick H | BMC medical genetics | 2009 | PMID: 19508727 |
Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia. | Brakensiek K | Clinical genetics | 2008 | PMID: 18498373 |
Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients. | Lesca G | European journal of human genetics : EJHG | 2008 | PMID: 18285823 |
Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. | Olivieri C | Journal of human genetics | 2007 | PMID: 17786384 |
Screening for children from families with Rendu-Osler-Weber disease: from geneticist to clinician. | Giordano P | Journal of thrombosis and haemostasis : JTH | 2006 | PMID: 16706966 |
DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. | Lenato GM | Human mutation | 2006 | PMID: 16429404 |
High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. | Schulte C | Human mutation | 2005 | PMID: 15880681 |
Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. | Harrison RE | Journal of medical genetics | 2003 | PMID: 14684682 |
Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia. | Olivieri C | Journal of medical genetics | 2002 | PMID: 12114496 |
Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1. | Lux A | The Journal of biological chemistry | 1999 | PMID: 10187774 |
The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. | Berg JN | American journal of human genetics | 1997 | PMID: 9245985 |
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Text-mined citations for rs863223414 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.