ClinVar Genomic variation as it relates to human health
NM_001613.4(ACTA2):c.116G>A (p.Arg39His)
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_001613.4(ACTA2):c.116G>A (p.Arg39His)
Variation ID: 199666 Accession: VCV000199666.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q23.31 10: 88948815 (GRCh38) [ NCBI UCSC ] 10: 90708572 (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 May 29, 2016 Feb 14, 2024 Dec 13, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001613.4:c.116G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001604.1:p.Arg39His missense NM_001141945.3:c.116G>A NP_001135417.1:p.Arg39His missense NM_001320855.2:c.116G>A NP_001307784.1:p.Arg39His missense NM_001406462.1:c.116G>A NP_001393391.1:p.Arg39His missense NM_001406463.1:c.116G>A NP_001393392.1:p.Arg39His missense NM_001406464.1:c.116G>A NP_001393393.1:p.Arg39His missense NM_001406466.1:c.116G>A NP_001393395.1:p.Arg39His missense NM_001406467.1:c.116G>A NP_001393396.1:p.Arg39His missense NM_001406468.1:c.116G>A NP_001393397.1:p.Arg39His missense NM_001406469.1:c.116G>A NP_001393398.1:p.Arg39His missense NM_001406471.1:c.116G>A NP_001393400.1:p.Arg39His missense NC_000010.11:g.88948815C>T NC_000010.10:g.90708572C>T NG_011541.1:g.47576G>A LRG_781:g.47576G>A LRG_781t1:c.116G>A LRG_781p1:p.Arg39His LRG_781t2:c.116G>A LRG_781p2:p.Arg39His P62736:p.Arg39His - Protein change
- R39H
- Other names
- p.R39H:CGT>CAT
- Canonical SPDI
- NC_000010.11:88948814:C:T
-
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. |
|||
ACTA2 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
312 | 578 |
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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 9, 2022 | RCV000181015.14 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 13, 2023 | RCV000533011.14 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 24, 2018 | RCV000779683.9 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 15, 2020 | RCV000770644.11 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Oct 04, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000902098.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
|
|
Likely pathogenic
(Sep 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial aortopathy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916411.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: ACTA2 c.116G>A (p.Arg39His) results in a non-conservative amino acid change affecting a highly conserved residue located in the subdomain 2 (SD2) of the … (more)
Variant summary: ACTA2 c.116G>A (p.Arg39His) results in a non-conservative amino acid change affecting a highly conserved residue located in the subdomain 2 (SD2) of the encoded protein sequence, whose dynamics are essential for ATP hydrolysis (Guo 2009). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121750 control chromosomes (ExAC and publication data). The variant has been reported in two unrelated families with multiple affected family members who had TAAD, Type A or Type B aortic dissection, coronary artery disease, patent ductus arteriosus, and/or stroke (Guo 2009), however, only ACTA2 was screened for in these families, and one unaffected individual, above the average age of onset for aortopathy (20 y/o), from each family was identified as a carrier of R39H. After contacting the corresponding author for this paper, they indicated that there has been no addtional follow-up with the discordant members from the two families carrying the variant of interest since the publication. The variant was also reported recently in a patient with aortic dissection, and in his father with aortic aneurism (Overwater 2018). In addition, the variant was identified in an internal specimen (18 month old female whose phenotype is unknown), whose mother was indicated to be a carrier of the variant of interest and presented with stroke, left MCA infarcts, history of hyperplastic vascular myopathy and aneurysms. A missense variant at the same position, R39C, was reported in patients with aortic aneurysm or mild aortic dilatation and insufficiency, indicating that R39 is a critical amino acid and changes at this position could affect function of ACTA2 (Hoffjan 2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (classifying the variant as Pathogenic, Likely pathogenic or VUS). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
Pathogenic
(Jul 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000927802.1
First in ClinVar: Jul 30, 2019 Last updated: Jul 30, 2019 |
|
|
Likely pathogenic
(May 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000738463.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R39H variant (also known as c.116G>A), located in coding exon 1 of the ACTA2 gene, results from a G to A substitution at nucleotide … (more)
The p.R39H variant (also known as c.116G>A), located in coding exon 1 of the ACTA2 gene, results from a G to A substitution at nucleotide position 116. The arginine at codon 39 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in multiple unrelated individuals with ACTA2-related vascular phenotypes (Guo DC et al, Am. J. Hum. Genet. 2009 May; 84(5):617-27; Regalado ES et al, Am. J. Med. Genet. A 2014 Jan; 164A(1):106-12; Yang H et al. Sci Rep, 2016 09;6:33002; Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192; GeneDx pers. comm.; Invitae pers. comm.). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Jun 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000233289.16
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Has been reported in association with aortic dissection or aortopathy (Regalado et al., 2014; Yang et al., 2016); Not observed at significant frequency in large … (more)
Has been reported in association with aortic dissection or aortopathy (Regalado et al., 2014; Yang et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); 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: 19409525, 21248741, 27611364, 26934405, 24243736, 26153420, 20689142, 29907982, 21937134, 21212136) (less)
|
|
Likely pathogenic
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic aneurysm, familial thoracic 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004242458.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PM5_STR,PS4_MOD,PM2_SUP,PP2,PP3
Clinical Features:
Ascending aortic dissection (present) , Abnormal arterial physiology (present) , Abnormal aortic valve physiology (present)
Sex: female
|
|
Pathogenic
(Jan 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic aneurysm, familial thoracic 6
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000646311.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 39 of the ACTA2 protein (p.Arg39His). This missense change has been observed in individuals with aortic dissections (PMID: 19409525, 27611364; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. 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: 21248741, 21733706, 21937134, 24243736, 25644172, 25759435). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt ACTA2 protein function. ClinVar contains an entry for this variant (Variation ID: 199666). (less)
|
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 |
---|---|---|---|---|
Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. | Overwater E | Human mutation | 2018 | PMID: 29907982 |
Genetic testing of 248 Chinese aortopathy patients using a panel assay. | Yang H | Scientific reports | 2016 | PMID: 27611364 |
Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin. | Lu H | Proceedings of the National Academy of Sciences of the United States of America | 2015 | PMID: 26153420 |
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 |
Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2). | Disabella E | Heart (British Cardiac Society) | 2011 | PMID: 21212136 |
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 |
click to load more click to collapse |
Text-mined citations for rs794728021 ...
HelpRecord last updated Mar 23, 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.