ClinVar Genomic variation as it relates to human health
NM_001613.4(ACTA2):c.977C>A (p.Thr326Asn)
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.977C>A (p.Thr326Asn)
Variation ID: 263430 Accession: VCV000263430.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 88938074 (GRCh38) [ NCBI UCSC ] 10: 90697831 (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 Oct 3, 2016 Apr 20, 2024 Dec 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001613.4:c.977C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001604.1:p.Thr326Asn missense NM_001141945.3:c.977C>A NP_001135417.1:p.Thr326Asn missense NM_001320855.2:c.977C>A NP_001307784.1:p.Thr326Asn missense NM_001406462.1:c.977C>A NP_001393391.1:p.Thr326Asn missense NM_001406463.1:c.977C>A NP_001393392.1:p.Thr326Asn missense NM_001406464.1:c.977C>A NP_001393393.1:p.Thr326Asn missense NM_001406466.1:c.866C>A NP_001393395.1:p.Thr289Asn missense NM_001406467.1:c.848C>A NP_001393396.1:p.Thr283Asn missense NM_001406468.1:c.848C>A NP_001393397.1:p.Thr283Asn missense NM_001406469.1:c.848C>A NP_001393398.1:p.Thr283Asn missense NM_001406471.1:c.785C>A NP_001393400.1:p.Thr262Asn missense NC_000010.11:g.88938074G>T NC_000010.10:g.90697831G>T NG_011541.1:g.58317C>A LRG_781:g.58317C>A LRG_781t1:c.977C>A LRG_781p1:p.Thr326Asn LRG_781t2:c.977C>A LRG_781p2:p.Thr326Asn P62736:p.Thr326Asn - Protein change
- T326N, T289N, T262N, T283N
- Other names
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- Canonical SPDI
- NC_000010.11:88938073:G:T
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00013
The Genome Aggregation Database (gnomAD), exomes 0.00006
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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 | ||
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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
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. |
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ACTA2 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
329 | 615 | |
ACTA2-AS1 | - | - | - | GRCh38 | - | 236 |
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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Oct 18, 2023 | RCV000528827.12 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Sep 15, 2023 | RCV000788708.13 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 28, 2023 | RCV001179388.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 30, 2019 | RCV001194246.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 8, 2021 | RCV002487139.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 20, 2023 | RCV003897585.1 |
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. |
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Uncertain significance
(Sep 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000927914.1
First in ClinVar: Jul 30, 2019 Last updated: Jul 30, 2019 |
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Uncertain significance
(Sep 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363634.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: ACTA2 c.977C>A (p.Thr326Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: ACTA2 c.977C>A (p.Thr326Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250886 control chromosomes. The observed variant frequency is approximately 3.4 fold the estimated maximal expected allele frequency for a pathogenic variant in ACTA2 causing Aortopathy phenotype (1.8e-05), strongly suggesting that the variant is benign. c.977C>A has been reported in the literature in individuals affected with TAA, stroke, and myocardial infarction (Guo_2009, Gillis_2017). These data do not allow any conclusion about variant significance. 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. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. (less)
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Uncertain significance
(Aug 19, 2020)
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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: SCV000317897.6
First in ClinVar: Oct 03, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.T326N variant (also known as c.977C>A), located in coding exon 7 of the ACTA2 gene, results from a C to A substitution at nucleotide … (more)
The p.T326N variant (also known as c.977C>A), located in coding exon 7 of the ACTA2 gene, results from a C to A substitution at nucleotide position 977. The threonine at codon 326 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported in a proband with an ascending aortic aneurysm and bicuspid aortic valve (BAV) and son with stroke at age 25, a proband with myocardial infarct due coronary artery stenosis, and an additional proband with BAV (Guo DC et al, Am. J. Hum. Genet. 2009 May; 84(5):617-27; Gillis E et al. Front Physiol. 2017 Jun;8:400). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Nov 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Aortic aneurysm, familial thoracic 6
Multisystemic smooth muscle dysfunction syndrome Moyamoya disease 5
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002790019.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Mar 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002099594.3
First in ClinVar: Mar 04, 2022 Last updated: Jul 16, 2023 |
Comment:
Has been reported in one individual with coronary artery stenosis and unrelated individuals with bicuspid aortic valve and thoracic aortic aneurysm (Guo et al., 2009; … (more)
Has been reported in one individual with coronary artery stenosis and unrelated individuals with bicuspid aortic valve and thoracic aortic aneurysm (Guo et al., 2009; Gillis et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20689142, 28848449, 28659821, 36053285, 19409525) (less)
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Uncertain significance
(Oct 18, 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: SCV000646322.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 326 of the ACTA2 protein (p.Thr326Asn). … (more)
This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 326 of the ACTA2 protein (p.Thr326Asn). This variant is present in population databases (rs777832794, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of ACTA2-related conditions (PMID: 19409525, 28659821; Invitae). ClinVar contains an entry for this variant (Variation ID: 263430). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Dec 21, 2022)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001344042.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with asparagine at codon 326 of the ACTA2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with asparagine at codon 326 of the ACTA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with thoracic aortic aneurysm and aortic dissection or ACTA2-related conditions (PMID: 19409525, 28659821, 36053285, ClinVar SCV000646322.2). This variant has also been observed in four individuals who had no history of aortic dissection or surgical repair of aortic aneurysms (PMID: 25759435). This variant has been identified in 15/250886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Sep 15, 2023)
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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: SCV004564915.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The ACTA2 c.977C>A; p.Thr326Asn variant (rs777832794) is reported in the literature in individuals affected with bicuspid aortic valve, thoracic aortic aneurysm, and stroke (Gillis 2017, … (more)
The ACTA2 c.977C>A; p.Thr326Asn variant (rs777832794) is reported in the literature in individuals affected with bicuspid aortic valve, thoracic aortic aneurysm, and stroke (Gillis 2017, Guo 2009, Regalado 2015, van den Bersselaar 2022). This variant is also reported in ClinVar (Variation ID: 263430), and is found in the non-Finnish European population with an allele frequency of 0.013% (15/113270 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.504). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Gillis E et al. Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor. Front Physiol. 2017 Jun 13;8:400. PMID: 28659821. Guo DC et al. Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009 May;84(5):617-27. PMID: 19409525. Regalado ES et al. Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. Circ Cardiovasc Genet. 2015 Jun;8(3):457-64. PMID: 25759435. van den Bersselaar LM et al. Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort. Genet Med. 2022 Oct;24(10):2112-2122. PMID: 36053285. (less)
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Uncertain significance
(Dec 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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ACTA2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004712282.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The ACTA2 c.977C>A variant is predicted to result in the amino acid substitution p.Thr326Asn. This variant has been reported in three individuals from two families … (more)
The ACTA2 c.977C>A variant is predicted to result in the amino acid substitution p.Thr326Asn. This variant has been reported in three individuals from two families with symptoms consistent with ACTA2-related aortic disease (Guo et al. 2009. PubMed ID: 19409525). However, this variant has also been observed in four members of an additional family (median age: 55 years; range 35 -75 years) who were all negative for aortic aneurysm/dissection events at the time of study (Regalado et al. 2015. PubMed ID: 25759435). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain Significance
(Nov 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004840597.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces threonine with asparagine at codon 326 of the ACTA2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with asparagine at codon 326 of the ACTA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with thoracic aortic aneurysm and aortic dissection or ACTA2-related conditions (PMID: 19409525, 28659821, 36053285, ClinVar SCV000646322.2). This variant has also been observed in four individuals who had no history of aortic dissection or surgical repair of aortic aneurysms (PMID: 25759435). This variant has been identified in 15/250886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 12
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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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Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort. | van den Bersselaar LM | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 36053285 |
Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor. | Gillis E | Frontiers in physiology | 2017 | PMID: 28659821 |
Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. | Regalado ES | Circulation. Cardiovascular genetics | 2015 | PMID: 25759435 |
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 |
A method for studying shape change in children. | Goldstein H | Annals of human biology | 1978 | PMID: 646322 |
Text-mined citations for rs777832794 ...
HelpRecord last updated Apr 20, 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.