ClinVar Genomic variation as it relates to human health
NM_000020.3(ACVRL1):c.152G>A (p.Cys51Tyr)
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.152G>A (p.Cys51Tyr)
Variation ID: 212797 Accession: VCV000212797.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.13 12: 52306973 (GRCh37) [ NCBI UCSC ] 12: 51913189 (GRCh38) [ 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 Dec 24, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000020.3:c.152G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000011.2:p.Cys51Tyr missense NM_001077401.2:c.152G>A NP_001070869.1:p.Cys51Tyr missense NC_000012.12:g.51913189G>A NC_000012.11:g.52306973G>A NG_009549.1:g.10772G>A LRG_543:g.10772G>A LRG_543t1:c.152G>A LRG_543p1:p.Cys51Tyr P37023:p.Cys51Tyr - Protein change
- C51Y
- Other names
- p.C51Y:TGC>TAC
- Canonical SPDI
- NC_000012.12:51913188: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 |
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) |
criteria provided, single submitter
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Jul 19, 2022 | RCV000200161.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 24, 2022 | RCV001857712.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 1, 2022 | RCV002399717.1 |
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 19, 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: SCV000249627.15
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate p.(C51Y) disrupts protein trafficking and results in failure to express the protein at the cell surface and impaired signaling (Lux et … (more)
Published functional studies demonstrate p.(C51Y) disrupts protein trafficking and results in failure to express the protein at the cell surface and impaired signaling (Lux et al., 1999; Ricard et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17786384, 23722869, 16540754, 16706966, 16429404, 10187774, 15879500, 22028876, 15266205, 12114496, 32300199, 10694922, 20501893) (less)
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Pathogenic
(Dec 24, 2022)
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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: SCV002245977.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within the ACVRL1 protein ectodomain. Cysteine residues in … (more)
For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within the ACVRL1 protein ectodomain. Cysteine residues in this domain of ACVRL1 are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 22028876, 22718755, 22799562). In addition, missense substitutions within the ACVRL1 ectodomain affecting cysteine residues are overrepresented in patients with HHT (PMID: 20501893, 26176610 and www.hhtmutation.org). Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 20501893). 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. ClinVar contains an entry for this variant (Variation ID: 212797). This missense change has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (PMID: 10694922, 16429404, 23722869; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 51 of the ACVRL1 protein (p.Cys51Tyr). (less)
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Pathogenic
(Jun 01, 2022)
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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: SCV002705503.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.C51Y pathogenic mutation (also known as c.152G>A), located in coding exon 2 of the ACVRL1 gene, results from a G to A substitution at … (more)
The p.C51Y pathogenic mutation (also known as c.152G>A), located in coding exon 2 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 152. The cysteine at codon 51 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported in individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) (Olivieri C et al. Genet. Med., 2006 Mar;8:183-90; Canzonieri C et al. Genet. Med., 2014 Jan;16:3-10). An in vitro study showed that cells transfected with this mutation express a protein that is unable to reach the cell surface and cannot bind or respond to BMP9 (Ricard N et al. Blood, 2010 Sep;116:1604-12). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Guerois R et al. J. Mol. Biol., 2002 Jul;320:369-87; Scotti C et al. PLoS ONE, 2011 Oct;6:e26431). 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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Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. | Alaa El Din F | PloS one | 2015 | PMID: 26176610 |
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 |
Structure of the Alk1 extracellular domain and characterization of its bone morphogenetic protein (BMP) binding properties. | Mahlawat P | Biochemistry | 2012 | PMID: 22799562 |
Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex. | Townson SA | The Journal of biological chemistry | 2012 | PMID: 22718755 |
Bioinformatic analysis of pathogenic missense mutations of activin receptor like kinase 1 ectodomain. | Scotti C | PloS one | 2011 | PMID: 22028876 |
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 |
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 |
Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. | Guerois R | Journal of molecular biology | 2002 | PMID: 12079393 |
Novel missense and frameshift mutations in the activin receptor-like kinase-1 gene in hereditary hemorrhagic telangiectasia. Mutations in brief no. 164. Online. | Klaus DJ | Human mutation | 1998 | PMID: 10694922 |
Text-mined citations for rs863223409 ...
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.