ClinVar Genomic variation as it relates to human health
NM_001613.4(ACTA2):c.353G>A (p.Arg118Gln)
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.353G>A (p.Arg118Gln)
Variation ID: 199670 Accession: VCV000199670.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 88943813 (GRCh38) [ NCBI UCSC ] 10: 90703570 (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 Dec 19, 2017 Feb 14, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001613.4:c.353G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001604.1:p.Arg118Gln missense NM_001141945.3:c.353G>A NP_001135417.1:p.Arg118Gln missense NM_001320855.2:c.353G>A NP_001307784.1:p.Arg118Gln missense NM_001406462.1:c.353G>A NP_001393391.1:p.Arg118Gln missense NM_001406463.1:c.353G>A NP_001393392.1:p.Arg118Gln missense NM_001406464.1:c.353G>A NP_001393393.1:p.Arg118Gln missense NM_001406467.1:c.224G>A NP_001393396.1:p.Arg75Gln missense NM_001406468.1:c.224G>A NP_001393397.1:p.Arg75Gln missense NM_001406469.1:c.224G>A NP_001393398.1:p.Arg75Gln missense NM_001406471.1:c.353G>A NP_001393400.1:p.Arg118Gln missense NC_000010.11:g.88943813C>T NC_000010.10:g.90703570C>T NG_011541.1:g.52578G>A LRG_781:g.52578G>A LRG_781t1:c.353G>A LRG_781p1:p.Arg118Gln LRG_781t2:c.353G>A LRG_781p2:p.Arg118Gln P62736:p.Arg118Gln - Protein change
- R118Q, R75Q
- Other names
- p.R118Q:CGG>CAG
- Canonical SPDI
- NC_000010.11:88943812:C: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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
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 |
312 | - |
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
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. |
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Pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2021 | RCV000181019.16 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV000234479.22 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 23, 2020 | RCV000608387.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 23, 2021 | RCV002485186.8 |
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
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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Pathogenic
(Sep 22, 2016)
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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: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000710874.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Arg118Gln variant in ACTA2 has been reported in 3 individuals with thoraci c aortic aneurysms and dissections (TAAD) and segregated with disease in 6 … (more)
The p.Arg118Gln variant in ACTA2 has been reported in 3 individuals with thoraci c aortic aneurysms and dissections (TAAD) and segregated with disease in 6 affec ted relatives from 3 families (Guo 2007, Gou 2009, Bee 2012). Furthermore, 2 add itional relatives with premature coronary artery disease also carried the varian t (Gou 2009). This variant has also been identified in 1/111342 European chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs112602953). Studies on cultured smooth muscle cells (SMCs) derived fr om a heterozygous carrier of this variant suggest that this variant perturbs ACT A2 filament assembly or stability (Guo 2007). In summary, this variant meets cri teria to be classified as pathogenic for familial TAAD in an autosomal dominant manner based upon segregation studies, low frequency in controls and functional evidence. ACMG/AMP criteria applied: PP1_Strong, PM2, PS3_Moderate, PP4, PS4_Sup porting. (less)
Number of individuals with the variant: 11
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Likely pathogenic
(Dec 23, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001733780.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces arginine with glutamine at codon 118 of the ACTA2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 118 of the ACTA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in yeast and cultured smooth muscle cells have shown that this variant affects actin assembly or stability (PMID: 17994018, 21288906). It has been shown that this variant segregates with thoracic aortic aneurysm and aortic dissection (TAAD) in three families (PMID: 17994018, 19409525, 23099432). This variant has also been reported in 9 related individuals affected with TAAD and/or coronary artery disease (PMID: 32093627). This variant has been identified in 1/251034 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Aortic aneurysm, familial thoracic 6
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557626.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with familial thoracic aortic aneurysm 6 (MIM#611788), Moyamoya disease 5 (MIM#614042) and multisystemic smooth muscle dysfunction syndrome (MIM#613834) (PMID: 27551047, 28652363). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated actin domain (NCBI). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change to a tryptophan has been reported once as a VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with familial thoracic aortic aneurysm (ClinVar, PMID: 17994018, 25759435). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional study using smooth muscle cells suggested that variant perturbs ACTA2 filament assembly or stability (PMID: 17994018). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Dec 09, 2017)
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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: SCV000738465.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R118Q pathogenic mutation (also known as c.353G>A), located in coding exon 3 of the ACTA2 gene, results from a G to A substitution at … (more)
The p.R118Q pathogenic mutation (also known as c.353G>A), located in coding exon 3 of the ACTA2 gene, results from a G to A substitution at nucleotide position 353. The arginine at codon 118 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported to segregate with thoracic aortic aneurysm and dissection in multiple families (Guo DC et al. Nat. Genet., 2007 Dec;39:1488-93; Guo DC et al. Am. J. Hum. Genet., 2009 May;84:617-27; Bee KJ et al. Circ Cardiovasc Genet, 2012 Dec;5:621-9). Moreover, in vitro studies have suggested that this alteration would affect actin assembly (Guo DC et al. Nat. Genet., 2007 Dec;39:1488-93; Bergeron SE et al. J. Biol. Chem., 2011 Apr;286:11356-69). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 23, 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: SCV002784965.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 03, 2021)
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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: SCV000233293.17
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic by several other clinical laboratories (ClinVar Variant ID# 199670; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 17994018, 21288906, 23099432, 28848449, 29727688, 20734336, 20689142, 21248741, 22946110, 25759435, 19409525, 31447099, 34244757) (less)
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Pathogenic
(Jan 02, 2024)
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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: SCV000287173.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 118 of the ACTA2 protein (p.Arg118Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 118 of the ACTA2 protein (p.Arg118Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with increased risk of coronary artery disease and/or thoracic aortic dissections (PMID: 17994018, 19409525, 21248741, 25759435). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199670). 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. Experimental studies have shown that this missense change affects ACTA2 function (PMID: 21288906). 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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Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts. | Liu Z | Proceedings of the National Academy of Sciences of the United States of America | 2017 | PMID: 28652363 |
Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. | Regalado ES | Circulation. Cardiovascular genetics | 2015 | PMID: 25759435 |
TGFβRIIb mutations trigger aortic aneurysm pathogenesis by altering transforming growth factor β2 signal transduction. | Bee KJ | Circulation. Cardiovascular genetics | 2012 | PMID: 23099432 |
Allele-specific effects of thoracic aortic aneurysm and dissection alpha-smooth muscle actin mutations on actin function. | Bergeron SE | The Journal of biological chemistry | 2011 | PMID: 21288906 |
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 |
Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. | Guo DC | Nature genetics | 2007 | PMID: 17994018 |
Text-mined citations for rs112602953 ...
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.