ClinVar Genomic variation as it relates to human health
NM_000020.3(ACVRL1):c.100T>C (p.Cys34Arg)
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.100T>C (p.Cys34Arg)
Variation ID: 1903167 Accession: VCV001903167.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.13 12: 51913137 (GRCh38) [ NCBI UCSC ] 12: 52306921 (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 Feb 7, 2023 Feb 28, 2024 May 24, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000020.3:c.100T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000011.2:p.Cys34Arg missense NM_001077401.2:c.100T>C NP_001070869.1:p.Cys34Arg missense NM_001406487.1:c.100T>C NP_001393416.1:p.Cys34Arg missense NM_001406488.1:c.100T>C NP_001393417.1:p.Cys34Arg missense NM_001406489.1:c.100T>C NP_001393418.1:p.Cys34Arg missense NM_001406490.1:c.100T>C NP_001393419.1:p.Cys34Arg missense NM_001406491.1:c.100T>C NP_001393420.1:p.Cys34Arg missense NM_001406492.1:c.100T>C NP_001393421.1:p.Cys34Arg missense NM_001406493.1:c.100T>C NP_001393422.1:p.Cys34Arg missense NM_001406494.1:c.100T>C NP_001393423.1:p.Cys34Arg missense NC_000012.12:g.51913137T>C NC_000012.11:g.52306921T>C NG_009549.1:g.10720T>C LRG_543:g.10720T>C LRG_543t1:c.100T>C LRG_543p1:p.Cys34Arg - Protein change
- C34R
- Other names
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- Canonical SPDI
- NC_000012.12:51913136:T:C
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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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- Links
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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May 24, 2022 | RCV002583485.2 |
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
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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
(May 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: SCV002931445.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 34 of the ACVRL1 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 34 of the ACVRL1 protein (p.Cys34Arg). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys34 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 16752392), which suggests that this may be a clinically significant amino acid residue. 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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). (less)
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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 |
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 |
Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. | Bossler AD | Human mutation | 2006 | PMID: 16752392 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 29, 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.