ClinVar Genomic variation as it relates to human health
NM_000020.3(ACVRL1):c.199C>T (p.Arg67Trp)
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.199C>T (p.Arg67Trp)
Variation ID: 426010 Accession: VCV000426010.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.13 12: 51913236 (GRCh38) [ NCBI UCSC ] 12: 52307020 (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 May 14, 2017 Mar 16, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000020.3:c.199C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000011.2:p.Arg67Trp missense NM_001077401.2:c.199C>T NP_001070869.1:p.Arg67Trp missense NC_000012.12:g.51913236C>T NC_000012.11:g.52307020C>T NG_009549.1:g.10819C>T LRG_543:g.10819C>T LRG_543t1:c.199C>T LRG_543p1:p.Arg67Trp - Protein change
- R67W
- Other names
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- Canonical SPDI
- NC_000012.12:51913235:C:T
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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.
The Genome Aggregation Database (gnomAD) 0.00001
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 |
987 | 998 |
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
Help
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 (1) |
no assertion criteria provided
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- | RCV000488479.2 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 9, 2024 | RCV001050243.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2021 | RCV002287412.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2021 | RCV002244957.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 17, 2021 | RCV002420248.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2023 | RCV003900028.1 |
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
Help
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
(Oct 04, 2021)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002050163.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The ACVRL1 c.199C>T;p.Arg67Trp variant (rs1085307405) has been described in the medical literature in several individuals and families diagnosed with hereditary hemorrhagic telangiectasia (see link to … (more)
The ACVRL1 c.199C>T;p.Arg67Trp variant (rs1085307405) has been described in the medical literature in several individuals and families diagnosed with hereditary hemorrhagic telangiectasia (see link to database and references therein, Ha 2012, Samol 2012) as well as one individual diagnosed with pulmonary arterial hypertension (Zhu 2019). The variant is listed in the ClinVar database (Variation ID: 426010), but absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 67 is highly conserved, occurs in a functional domain (Scotti 2011), and computational analyses predict that this variant is deleterious (REVEL: 0.723). Based on available information, this variant is considered to be pathogenic. References: Link to ACVRL1 database: http://arup.utah.edu/database/ACVRL1/ACVRL1_display.php Ha M et al. Gastric angiodysplasia in a hereditary hemorrhagic telangiectasia type 2 patient. World J Gastroenterol. 2012 Apr 21;18(15):1840-4. PMID: 22553411. Samol A et al. A rare cause of fatal right ventricular cardiac decompensation. Cardiovasc Pathol. 2012 Nov-Dec;21(6):515-8.. PMID: 22377182. Scotti C et al. Bioinformatic analysis of pathogenic missense mutations of activin receptor like kinase 1 ectodomain. PLoS One. 2011;6(10):e26431. PMID: 22028876. Zhu N et al. Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension. Genome Med. 2019 Nov 14;11(1):69. PMID: 31727138. (less)
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Likely pathogenic
(Aug 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Telangiectasia, hereditary hemorrhagic, type 2
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580362.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Dec 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the pulmonary vasculature
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002577805.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
ACMG categories: PM1,PM2,PP3,PP4,PP5
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the pulmonary vasculature (present)
Age: 40-49 years
Sex: female
Tissue: blood
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Pathogenic
(May 17, 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: SCV002721785.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R67W pathogenic mutation (also known as c.199C>T), located in coding exon 2 of the ACVRL1 gene, results from a C to T substitution at … (more)
The p.R67W pathogenic mutation (also known as c.199C>T), located in coding exon 2 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 199. The arginine at codon 67 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation was originally detected in two unrelated individuals who both presented with telangiectasias and extensive liver involvement (Olivieri C et al. J. Med. Genet., 2002 Jul;39:E39). This mutation was also described in two individuals who both were scheduled for liver transplants due to hepatic arteriovenous malformations. One individual also had epistaxis and telangiectasias while the other presented with gastrointestinal bleeding and angiectasias (Argyriou L et al. Liver Transpl., 2005 Sep;11:1132-5). It was also reported in multiple individuals with hereditary hemorrhagic telangiectasia (HHT) by independent studies (Ha M et al. World J. Gastroenterol., 2012 Apr;18:1840-4; Samol A et al. Cardiovasc. Pathol.;21:515-8). In addition, an alteration at the same amino acid position, p.R67Q, was also reported in individuals with HHT (Berg JN et al. Am. J. Hum. Genet., 1997 Jul;61:60-7; Canzonieri C et al. Genet. Med., 2014 Jan;16:3-10). Functional studies suggested that the p.R67Q variant abolishes both basal and serum-induced signaling activity in R-1B cells (Lux A et al. J. Biol. Chem., 1999 Apr;274:9984-92). 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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Likely pathogenic
(Dec 02, 2021)
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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: SCV002513707.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); 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, 34134972, 22553411, 31727138, 15712271, 16123970, 12114496, 23919827, 15266205, 17786384, 18285823, 16525724, 31455059, 20414677, 22377182) (less)
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Pathogenic
(Jan 09, 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: SCV001214342.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 67 of the ACVRL1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 67 of the ACVRL1 protein (p.Arg67Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 12114496, 15712271, 16123970, 22377182, 22553411). ClinVar contains an entry for this variant (Variation ID: 426010). 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%. 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: 9245985, 15880681, 16706966, 17786384, 18498373, 23722869). 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
(Nov 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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ACVRL1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004708377.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The ACVRL1 c.199C>T variant is predicted to result in the amino acid substitution p.Arg67Trp. This variant has been reported in multiple individuals with hereditary hemorrhagic … (more)
The ACVRL1 c.199C>T variant is predicted to result in the amino acid substitution p.Arg67Trp. This variant has been reported in multiple individuals with hereditary hemorrhagic telangiectasia (HTT) (Olivieri et al. 2002. PubMed ID: 12114496; Ha et al. 2012. PubMed ID: 22553411; Samol et al. 2012. PubMed ID: 22377182) and in a patient with HHT with pulmonary arterial hypertension (Table S3 in Zhu. 2019. PubMed ID: 31727138). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-52307020-C-T) and has been interpreted as pathogenic and likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/426010/). This variant is interpreted as pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: literature only
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Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia
Affected status: yes
Allele origin:
germline
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Rare Disease Genomics Group, St George's University of London
Accession: SCV000576315.1
First in ClinVar: May 14, 2017 Last updated: May 14, 2017 |
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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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Current Status of Clinical Diagnosis and Genetic Analysis of Hereditary Hemorrhagic Telangiectasia in South Korea: Multicenter Case Series and a Systematic Review. | Kim D | Neurointervention | 2019 | PMID: 31455059 |
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 |
Clinical and genetic characteristics of Chinese patients with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension. | Chen YJ | European journal of clinical investigation | 2013 | PMID: 23919827 |
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 |
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 |
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 |
Novel mutations in the ENG and ACVRL1 genes causing hereditary hemorrhagic teleangiectasia. | Argyriou L | International journal of molecular medicine | 2006 | PMID: 16525724 |
ALK-1 mutations in liver transplanted patients with hereditary hemorrhagic telangiectasia. | Argyriou L | Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society | 2005 | PMID: 16123970 |
High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. | Schulte C | Human mutation | 2005 | PMID: 15880681 |
Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. | Abdalla SA | Human mutation | 2005 | PMID: 15712271 |
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 rs1085307405 ...
HelpRecord last updated Mar 17, 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.