ClinVar Genomic variation as it relates to human health
NM_000020.3(ACVRL1):c.145dup (p.Ala49fs)
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
-
NM_000020.3(ACVRL1):c.145dup (p.Ala49fs)
Variation ID: 212805 Accession: VCV000212805.16
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 12q13.13 12: 51913176-51913177 (GRCh38) [ NCBI UCSC ] 12: 52306960-52306961 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 7, 2017 Apr 15, 2024 Dec 12, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000020.3:c.145dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000011.2:p.Ala49fs frameshift NM_000020.2:c.145dupG NM_001077401.2:c.145dup NP_001070869.1:p.Ala49fs frameshift NC_000012.12:g.51913182dup NC_000012.11:g.52306966dup NG_009549.1:g.10765dup LRG_543:g.10765dup LRG_543t1:c.145dup LRG_543p1:p.Ala49fs - Protein change
- A49fs
- Other names
- -
- Canonical SPDI
- NC_000012.12:51913176:GGGGGG:GGGGGGG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
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. |
|||
ACVRL1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
985 | 996 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 1, 2023 | RCV000195435.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 11, 2023 | RCV000459586.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 1, 2021 | RCV002390511.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 12, 2023 | RCV003895254.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 19, 2023 | RCV003235117.1 |
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
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. |
|
---|---|---|---|---|---|
Pathogenic
(May 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002697149.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.145dupG pathogenic mutation (also known as 140dupG), located in coding exon 2 of the ACVRL1 gene, results from a duplication of G at nucleotide … (more)
The c.145dupG pathogenic mutation (also known as 140dupG), located in coding exon 2 of the ACVRL1 gene, results from a duplication of G at nucleotide position 145, causing a translational frameshift with a predicted alternate stop codon (p.A49Gfs*120). This mutation has been identified in multiple individuals and families meeting criteria for hereditary hemorrhagic telangiectasia (Klaus DJ et al. Hum. Mutat., 1998;12:137; Olivieri C et al. J. Hum. Genet., 2007 Sep;52:820-9; Fontalba A et al. BMC Med. Genet., 2008 Aug;9:75; McDonald J et al. Clin. Genet., 2011 Apr;79:335-44). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Jan 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000249636.10
First in ClinVar: Oct 11, 2015 Last updated: Jan 15, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as 140insG, c.144_145insG and c.145_146insG; This variant is associated with the following publications: (PMID: 15266205, 15879500, 10694922, 17786384, 12114496, 23805858, 32300199, 18673552, 19508727) (less)
|
|
Pathogenic
(May 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
ACVRL1-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934610.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: ACVRL1 c.145dupG (p.Ala49GlyfsX120) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ACVRL1 c.145dupG (p.Ala49GlyfsX120) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 221746 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.145dupG has been reported in the literature in individuals affected with Hereditary Hemorrhagic Telangiectasia (e.g., Sadick_2009, Fontalba_2008). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18673552, 19508727). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Telangiectasia, hereditary hemorrhagic, type 2
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000552418.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ala49Glyfs*120) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ala49Glyfs*120) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (HHT) (PMID: 10694922, 12114496). ClinVar contains an entry for this variant (Variation ID: 212805). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
ACVRL1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004711887.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The ACVRL1 c.145dupG variant is predicted to result in a frameshift and premature protein termination (p.Ala49Glyfs*120). This variant was reported in individuals with hereditary hemorrhagic … (more)
The ACVRL1 c.145dupG variant is predicted to result in a frameshift and premature protein termination (p.Ala49Glyfs*120). This variant was reported in individuals with hereditary hemorrhagic telangiectasia (HHT) (Table S1 in McDonald et al 2020. PubMed ID: 32300199; Sadick et al. 2009. PubMed ID: 19508727; Fontalba et al. 2008. PubMed ID: 18673552). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in ACVRL1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
Pathogenic
(Oct 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004133331.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
ACVRL1: PVS1, PM2, PS4:Moderate
Number of individuals with the variant: 1
|
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 |
---|---|---|---|---|
Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. | McDonald J | Clinical genetics | 2011 | PMID: 21158752 |
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 |
Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia. | Fontalba A | BMC medical genetics | 2008 | PMID: 18673552 |
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 |
Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. | Abdalla SA | Journal of medical genetics | 2006 | PMID: 15879500 |
Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. | Bayrak-Toydemir P | Genetics in medicine : official journal of the American College of Medical Genetics | 2004 | PMID: 15266205 |
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 |
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 rs863223415 ...
HelpRecord last updated Apr 15, 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.