ClinVar Genomic variation as it relates to human health
NM_001613.4(ACTA2):c.115C>G (p.Arg39Gly)
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_001613.4(ACTA2):c.115C>G (p.Arg39Gly)
Variation ID: 199665 Accession: VCV000199665.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 88948816 (GRCh38) [ NCBI UCSC ] 10: 90708573 (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 28, 2018 Feb 14, 2024 Aug 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001613.4:c.115C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001604.1:p.Arg39Gly missense NM_001141945.3:c.115C>G NP_001135417.1:p.Arg39Gly missense NM_001320855.2:c.115C>G NP_001307784.1:p.Arg39Gly missense NM_001406462.1:c.115C>G NP_001393391.1:p.Arg39Gly missense NM_001406463.1:c.115C>G NP_001393392.1:p.Arg39Gly missense NM_001406464.1:c.115C>G NP_001393393.1:p.Arg39Gly missense NM_001406466.1:c.115C>G NP_001393395.1:p.Arg39Gly missense NM_001406467.1:c.115C>G NP_001393396.1:p.Arg39Gly missense NM_001406468.1:c.115C>G NP_001393397.1:p.Arg39Gly missense NM_001406469.1:c.115C>G NP_001393398.1:p.Arg39Gly missense NM_001406471.1:c.115C>G NP_001393400.1:p.Arg39Gly missense NC_000010.11:g.88948816G>C NC_000010.10:g.90708573G>C NG_011541.1:g.47575C>G LRG_781:g.47575C>G LRG_781t1:c.115C>G LRG_781p1:p.Arg39Gly LRG_781t2:c.115C>G LRG_781p2:p.Arg39Gly - Protein change
- R39G
- Other names
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- Canonical SPDI
- NC_000010.11:88948815:G: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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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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ACTA2 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
312 | 577 |
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
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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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Aug 28, 2023 | RCV000645628.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 3, 2021 | RCV001812161.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 1, 2018 | RCV002372107.8 |
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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Likely pathogenic
(Jun 03, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002050093.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The ACTA2 c.115C>G; p.Arg39Gly variant (rs112901682) is reported in the literature in a family affected with aortic disease (Regalado 2015). This variant is absent from … (more)
The ACTA2 c.115C>G; p.Arg39Gly variant (rs112901682) is reported in the literature in a family affected with aortic disease (Regalado 2015). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 39 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.844). Additionally, other amino acid substitutions at this codon (p.Arg39Cys and p.Arg39His) have been reported in individuals with aortic aneurysm and dissection and are considered pathogenic (Hoffjan 2011, Overwater 2018, Regalado 2015). Based on available information, the p.Arg39Gly variant is considered to be likely pathogenic. References: Hoffjan S et al. Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. Eur J Hum Genet. 2011 May;19(5):520-4. PMID: 21248741. Overwater E et al. Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. Hum Mutat. 2018 Sep;39(9):1173-1192. PMID: 29907982. Regalado et al. Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. Circ Cardiovasc Genet. 2015 Jun;8(3):457-64. PMID: 25759435. (less)
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Likely pathogenic
(Jun 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002625120.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R39G variant (also known as c.115C>G), located in coding exon 1 of the ACTA2 gene, results from a C to G substitution at nucleotide … (more)
The p.R39G variant (also known as c.115C>G), located in coding exon 1 of the ACTA2 gene, results from a C to G substitution at nucleotide position 115. The arginine at codon 39 is replaced by glycine, an amino acid with dissimilar properties. This amino acid is located in the SD2 domain, whose dynamics are essential for ATP hydrolysis (Guo DC et al. Am J Hum Genet. 2009;84(5):617-27). In one family, this variant was described in 14 individuals, four of whom were reported to have had aortic dissection and/or surgical repair of aortic aneurysm (Regalado ES et al. Circ Cardiovasc Genet. 2015;8(3):457-64). Two other alterations of the same codon, p.R39C (c.115C>T) and p.R39H (c.116G>A), have been reported. The p.R39C alteration was reported in a family with recurrent aortic aneurysm (Hoffjan S et al. Eur J Hum Genet. 2011;19(5):520-4), while the p.R39H alteration was reported in two families with thoracic aortic aneurysms and dissections as well as premature stroke and coronary artery disease (Guo DC et al. Am J Hum Genet. 2009;84(5):617-27). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, the p.R39G variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Aortic aneurysm, familial thoracic 6
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000767378.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 39 of the ACTA2 protein (p.Arg39Gly). … (more)
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 39 of the ACTA2 protein (p.Arg39Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ACTA2-related conditions (PMID: 25759435; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199665). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACTA2 protein function. This variant disrupts the p.Arg39 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19409525, 21248741, 21733706, 21937134, 24243736, 25644172, 25759435, 27611364; Invitae). 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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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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Genetic testing of 248 Chinese aortopathy patients using a panel assay. | Yang H | Scientific reports | 2016 | PMID: 27611364 |
Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. | Regalado ES | Circulation. Cardiovascular genetics | 2015 | PMID: 25759435 |
Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. | Campens L | Orphanet journal of rare diseases | 2015 | PMID: 25644172 |
Acute aortic dissections with pregnancy in women with ACTA2 mutations. | Regalado ES | American journal of medical genetics. Part A | 2014 | PMID: 24243736 |
Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD. | Renard M | International journal of cardiology | 2013 | PMID: 21937134 |
Isolated giant ascending aortic aneurysm in a child: a novel mutation of the ACTA2 gene. | Imai T | European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery | 2011 | PMID: 21733706 |
Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. | Hoffjan S | European journal of human genetics : EJHG | 2011 | PMID: 21248741 |
Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. | Guo DC | American journal of human genetics | 2009 | PMID: 19409525 |
Text-mined citations for rs112901682 ...
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.