ClinVar Genomic variation as it relates to human health
NM_000020.3(ACVRL1):c.1450C>T (p.Arg484Trp)
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.1450C>T (p.Arg484Trp)
Variation ID: 8252 Accession: VCV000008252.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.13 12: 51920831 (GRCh38) [ NCBI UCSC ] 12: 52314615 (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 May 1, 2024 Dec 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000020.3:c.1450C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000011.2:p.Arg484Trp missense NM_001077401.2:c.1450C>T NP_001070869.1:p.Arg484Trp missense NC_000012.12:g.51920831C>T NC_000012.11:g.52314615C>T NG_009549.1:g.18414C>T LRG_543:g.18414C>T LRG_543t1:c.1450C>T LRG_543p1:p.Arg484Trp P37023:p.Arg484Trp - Protein change
- R484W
- Other names
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- Canonical SPDI
- NC_000012.12:51920830: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
Help
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 |
1001 | 1012 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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 (3) |
criteria provided, single submitter
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Jul 19, 2017 | RCV000008740.5 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 16, 2023 | RCV000008739.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2016 | RCV000507762.8 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001003756.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2022 | RCV001564363.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 14, 2017 | RCV002390099.2 |
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
Help
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
Help
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
(Dec 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602426.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Aug 14, 2017)
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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: SCV002696865.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R484W pathogenic mutation (also known as c.1450C>T), located in coding exon 9 of the ACVRL1 gene, results from a C to T substitution at … (more)
The p.R484W pathogenic mutation (also known as c.1450C>T), located in coding exon 9 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1450. The arginine at codon 484 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was first reported in three related individuals with symptoms of hereditary hemorrhagic telangiectasia and pulmonary hypertension (Trembath RC et al. N. Engl. J. Med., 2001 Aug;345:325-34). In addition, this alteration has been reported in multiple individuals who met Curaçao criteria for HHT (Lesca G et al. Hum. Mutat., 2004 Apr;23:289-99; Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16; Lenato GM et al. Hum. Mutat., 2006 Feb;27:213-4). An in vitro functional study found this alteration caused the protein to be retained in the endoplasmic reticulum and not transported to the cell membrane (Hume AN et al. Mol. Cell. Biochem., 2013 Jan;373:247-57). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996066.1
First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019 |
Comment:
This missense variant is found in exon 10 of the ACVRL1 gene. This variant, as well as another pathogenic variant at the same amino acid … (more)
This missense variant is found in exon 10 of the ACVRL1 gene. This variant, as well as another pathogenic variant at the same amino acid position, are well reported in the literature. The p.Arg484Trp variant has been reported in at least five cases from three independent families in the literature in patients with HHT (PMID: 11484689, 15024723, 27316748). Functional studies have shown that the p.Arg484Trp variant, which lies in the intracellular kinase domain, negatively affects trafficking in the endoplasmic reticulum in HHT patients (PMID: 23124896). The variant is not found in any allele frequency databases. Thus, it is presumed to be rare. Based on the available evidence, this variant is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 26, 2021)
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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: SCV002103249.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
PM6_very strong, PS3, PS4_moderate, PM5, PM1, PM2, PP3, PP2
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Pathogenic
(May 11, 2022)
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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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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556722.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Oct 03, 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: SCV001787519.3
First in ClinVar: Aug 19, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect and suggest functional haploinsufficiency as the mechanism of … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect and suggest functional haploinsufficiency as the mechanism of disease (Ricard et al., 2010; Piao et al., 2016); 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: 11484689, 15266205, 26387786, 29449337, 23124896, 18673552, 25970827, 16282348, 15024723, 15517393, 18285823, 15879500, 16429404, 12114496, 16690726, 16540754, 14684682, 17786384, 27316748, 30303062, 29650961, 29743074, 31727138, 27587546, 31019026, 32581362, 32300199, 30578383, 20501893, 32503579, 35346192) (less)
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Pathogenic
(Dec 16, 2023)
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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: SCV002228950.3
First in ClinVar: Mar 28, 2022 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 484 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 484 of the ACVRL1 protein (p.Arg484Trp). This variant is present in population databases (rs121909288, gnomAD 0.007%). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia or pulmonary hypertension (PMID: 11484689, 29449337). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8252). 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, 23124896, 27316748). This variant disrupts the p.Arg484 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15687131, 17786384, 20501893, 21378382, 23919827). 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
(-)
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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: SCV000576347.1
First in ClinVar: May 13, 2017 Last updated: May 13, 2017 |
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Pathogenic
(Aug 02, 2001)
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no assertion criteria provided
Method: literature only
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TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028948.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Trembath et al. (2001) identified an arg484-to-trp (R484W) mutation in exon 10 of … (more)
In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Trembath et al. (2001) identified an arg484-to-trp (R484W) mutation in exon 10 of the ACVRL1 gene. Two patients had isolated HHT, 2 had isolated pulmonary arterial hypertension, and 1 had both HHT and pulmonary hypertension (see 600376). Trembath et al. (2001) noted that the arginine residue at this position is conserved in mouse and human ACVRL1 and in several human paralogs. (less)
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Pathogenic
(Aug 02, 2001)
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no assertion criteria provided
Method: literature only
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PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028949.2
First in ClinVar: Apr 04, 2013 Last updated: May 13, 2017 |
Comment on evidence:
In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Trembath et al. (2001) identified an arg484-to-trp (R484W) mutation in exon 10 of … (more)
In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Trembath et al. (2001) identified an arg484-to-trp (R484W) mutation in exon 10 of the ACVRL1 gene. Two patients had isolated HHT, 2 had isolated pulmonary arterial hypertension, and 1 had both HHT and pulmonary hypertension (see 600376). Trembath et al. (2001) noted that the arginine residue at this position is conserved in mouse and human ACVRL1 and in several human paralogs. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Pulmonary arterial hypertension
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162199.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: female
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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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Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
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 |
Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). | McDonald J | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32300199 |
Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation. | Clark MM | Science translational medicine | 2019 | PMID: 31019026 |
Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases. | Eyries M | The European respiratory journal | 2019 | PMID: 30578383 |
Paediatric pulmonary hypertension caused by an ACVRL1 mutation presenting as Ortner syndrome. | Alsheikh B | Cardiology in the young | 2018 | PMID: 30303062 |
Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients. | Yang H | Respiratory research | 2018 | PMID: 29743074 |
Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. | Gräf S | Nature communications | 2018 | PMID: 29650961 |
ALK1 Loss Results in Vascular Hyperplasia in Mice and Humans Through PI3K Activation. | Alsina-Sanchís E | Arteriosclerosis, thrombosis, and vascular biology | 2018 | PMID: 29449337 |
Genetic analyses in a cohort of children with pulmonary hypertension. | Levy M | The European respiratory journal | 2016 | PMID: 27587546 |
Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture. | Piao C | Clinical science (London, England : 1979) | 2016 | PMID: 27316748 |
Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1. | Heimdal K | Clinical genetics | 2016 | PMID: 25970827 |
Clinical and genetic characteristics of Chinese patients with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension. | Chen YJ | European journal of clinical investigation | 2013 | PMID: 23919827 |
Retention in the endoplasmic reticulum is the underlying mechanism of some hereditary haemorrhagic telangiectasia type 2 ALK1 missense mutations. | Hume AN | Molecular and cellular biochemistry | 2013 | PMID: 23124896 |
Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients. | Best DH | Journal of medical genetics | 2011 | PMID: 21378382 |
Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. | Ricard N | Blood | 2010 | PMID: 20501893 |
Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. | Girerd B | American journal of respiratory and critical care medicine | 2010 | PMID: 20056902 |
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 |
Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia. | Olivieri C | Genetics in medicine : official journal of the American College of Medical Genetics | 2006 | PMID: 16540754 |
DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. | Lenato GM | Human mutation | 2006 | PMID: 16429404 |
Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood. | Harrison RE | Circulation | 2005 | PMID: 15687131 |
Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. | Letteboer TG | Human genetics | 2005 | PMID: 15517393 |
Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. | Lesca G | Human mutation | 2004 | PMID: 15024723 |
Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. | Trembath RC | The New England journal of medicine | 2001 | PMID: 11484689 |
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Text-mined citations for rs121909288 ...
HelpRecord last updated May 01, 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.