ClinVar Genomic variation as it relates to human health
NM_001613.4(ACTA2):c.115C>T (p.Arg39Cys)
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.115C>T (p.Arg39Cys)
Variation ID: 65449 Accession: VCV000065449.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q23.31 10: 88948816 (GRCh38) [ NCBI UCSC ] 10: 90708573 (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 Sep 7, 2014 Mar 10, 2024 Oct 18, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001613.4:c.115C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001604.1:p.Arg39Cys missense NM_001141945.3:c.115C>T NP_001135417.1:p.Arg39Cys missense NM_001320855.2:c.115C>T NP_001307784.1:p.Arg39Cys missense NM_001406462.1:c.115C>T NP_001393391.1:p.Arg39Cys missense NM_001406463.1:c.115C>T NP_001393392.1:p.Arg39Cys missense NM_001406464.1:c.115C>T NP_001393393.1:p.Arg39Cys missense NM_001406466.1:c.115C>T NP_001393395.1:p.Arg39Cys missense NM_001406467.1:c.115C>T NP_001393396.1:p.Arg39Cys missense NM_001406468.1:c.115C>T NP_001393397.1:p.Arg39Cys missense NM_001406469.1:c.115C>T NP_001393398.1:p.Arg39Cys missense NM_001406471.1:c.115C>T NP_001393400.1:p.Arg39Cys missense NC_000010.11:g.88948816G>A NC_000010.10:g.90708573G>A NG_011541.1:g.47575C>T LRG_781:g.47575C>T LRG_781t1:c.115C>T LRG_781p1:p.Arg39Cys LRG_781t2:c.115C>T LRG_781p2:p.Arg39Cys - Protein change
- R39C
- Other names
- -
- Canonical SPDI
- NC_000010.11:88948815:G:A
-
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.
The Genome Aggregation Database (gnomAD) 0.00001
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 |
329 | 615 |
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, single submitter
|
Oct 18, 2023 | RCV000055647.39 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 17, 2019 | RCV000143866.8 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 23, 2023 | RCV000490091.11 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 18, 2022 | RCV002274892.3 |
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
(Jul 18, 2019)
|
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: SCV000902099.2 First in ClinVar: May 06, 2019 Last updated: Jan 01, 2022 |
|
|
Pathogenic
(Jul 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002562231.1
First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
Comment:
ACMG categories: PS4,PM1,PM2,PP1,PP3,PP5,BP1
Number of individuals with the variant: 1
Clinical Features:
Joint hypermobility (present) , Abnormality of connective tissue (present)
Age: 40-49 years
Sex: female
Tissue: blood
|
|
Pathogenic
(Sep 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002624318.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R39C variant (also known as c.115C>T), located in coding exon 1 of the ACTA2 gene, results from a C to T substitution at nucleotide … (more)
The p.R39C variant (also known as c.115C>T), located in coding exon 1 of the ACTA2 gene, results from a C to T substitution at nucleotide position 115. The arginine at codon 39 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with thoracic aortic aneurysm and dissection (TAAD), and co-segregation in affected relatives was reported in two unrelated families (Hoffjan S et al. Eur. J. Hum. Genet., 2011 May;19:520-4; Renard M et al. Int. J. Cardiol., 2013 May;165:314-21; Regalado ES et al. Am. J. Med. Genet. A, 2014 Jan;164A:106-12; Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). Alternate amino acid substitutions at this position, p.R39H and p.R39G, have also been associated with TAAD and vascular disease findings (Guo DC et al. Am J Hum Genet. 2009;84(5):617-27; Regalado ES et al. Circ Cardiovasc Genet. 2015;8(3):457-64). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(May 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000576794.7
First in ClinVar: May 22, 2017 Last updated: Jun 03, 2023 |
Comment:
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; … (more)
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: 21733706, 25644172, 25759435, 24243736, 21248741, 21937134, 30030203, 29907982, 31536524, 35567597, 36053285, 34498425) (less)
|
|
Pathogenic
(Oct 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic aneurysm, familial thoracic 6
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000646310.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 39 of the ACTA2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 39 of the ACTA2 protein (p.Arg39Cys). This variant is present in population databases (rs112901682, gnomAD 0.03%). This missense change has been observed in individuals with aortopathy (PMID: 21248741, 21733706, 21937134, 24243736, 25644172, 25759435). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65449). 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. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Feb 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564421.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The ACTA2 c.115C>T; p.Arg39Cys variant (rs112901682) is reported in multiple individuals with thoracic aortic disorders and shown to segregate with disease in affected family members … (more)
The ACTA2 c.115C>T; p.Arg39Cys variant (rs112901682) is reported in multiple individuals with thoracic aortic disorders and shown to segregate with disease in affected family members (Campens 2015, Hoffjan 2011, Kaw 2022, Li 2021, Overwater 2018). This variant is also reported in ClinVar (Variation ID: 65449). This variant is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.853). Additionally, other variants at this codon (p.Arg39Gly, p.Arg39His) are reported in individuals with aortic aneurysm and dissection and are considered to be causative (Hoffjan 2011, Overwater 2018, Regalado 2015). Based on available information, the p.Arg39Cys variant is considered to be pathogenic. References: Campens L et al. Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. Orphanet J Rare Dis. 2015 Feb 3;10:9. PMID: 25644172. 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. Kaw A et al. Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome. Am J Med Genet A. 2022 Aug;188(8):2389-2396. PMID: 35567597. Li J et al. Genetic testing and clinical relevance of patients with thoracic aortic aneurysm and dissection in northwestern China. Mol Genet Genomic Med. 2021 Oct;9(10):e1800. PMID: 34498425. 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 ES et al. Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. Circ Cardiovasc Genet. 2015 Jun;8(3):457-64. PMID: 25759435. (less)
|
|
Pathogenic
(Jan 30, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Thoracic aortic aneurysms and aortic dissections
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000188734.1
First in ClinVar: Sep 07, 2014 Last updated: Sep 07, 2014 |
|
|
Pathogenic
(May 01, 2011)
|
no assertion criteria provided
Method: literature only
|
AORTIC ANEURYSM, FAMILIAL THORACIC 6
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000083872.5
First in ClinVar: Sep 29, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In a 3-generation German family with autosomal dominant thoracic aortic aneurysm (AAT6; 611788), Hoffjan et al. (2011) identified heterozygosity for a c.115C-T transition in exon … (more)
In a 3-generation German family with autosomal dominant thoracic aortic aneurysm (AAT6; 611788), Hoffjan et al. (2011) identified heterozygosity for a c.115C-T transition in exon 2 of the ACTA2 gene, resulting in an arg39-to-cys (R39C) substitution at a highly conserved residue adjacent to the DNAse-I-binding loop within subdomain 2. The mutation segregated with disease in the family and was not found in 192 control chromosomes or in the GenBank dbSNP library. The vascular phenotype was variable in this family, ranging from mild aortic dilation and insufficiency in a 44-year-old woman to overt aortic aneurysm extending from the ascending to the abdominal aorta in a 25-year-old man. None of the affected individuals showed syndromic features, and there was no history of premature stroke or coronary artery disease. Hoffjan et al. (2011) noted that although a different mutation at the R39 residue, R39H, had been associated with type A dissections in 2 families and with type B dissections in another family (Guo et al., 2009), dissections were not observed in the family with the R39C mutation. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807981.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953652.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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 |
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 Mar 11, 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.