In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient referred for Marfan syndrome, Loeys-Dietz syndrome or TAAD genetic testing; detailed clinical information was not provided (Lerner-Ellis et al., 2014); This variant is associated with the following publications: (PMID: 24793577)
ClinVar Genomic variation as it relates to human health
NM_001613.4(ACTA2):c.607G>A (p.Val203Ile)
Germline
Classification
Help
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.
(7)
Help
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.
Uncertain significance
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001613.4(ACTA2):c.607G>A (p.Val203Ile)
Variation ID: 44218 Accession: VCV000044218.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q23.31 10: 88941238 (GRCh38) [ NCBI UCSC ] 10: 90700995 (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 Mar 8, 2017 Sep 16, 2024 Jun 26, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001613.4:c.607G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001604.1:p.Val203Ile missense NM_001141945.3:c.607G>A NP_001135417.1:p.Val203Ile missense NM_001320855.2:c.607G>A NP_001307784.1:p.Val203Ile missense NM_001406462.1:c.607G>A NP_001393391.1:p.Val203Ile missense NM_001406463.1:c.607G>A NP_001393392.1:p.Val203Ile missense NM_001406464.1:c.607G>A NP_001393393.1:p.Val203Ile missense NM_001406466.1:c.496G>A NP_001393395.1:p.Val166Ile missense NM_001406467.1:c.478G>A NP_001393396.1:p.Val160Ile missense NM_001406468.1:c.478G>A NP_001393397.1:p.Val160Ile missense NM_001406469.1:c.478G>A NP_001393398.1:p.Val160Ile missense NM_001406471.1:c.607G>A NP_001393400.1:p.Val203Ile missense NC_000010.11:g.88941238C>T NC_000010.10:g.90700995C>T NG_011541.1:g.55153G>A LRG_781:g.55153G>A LRG_781t1:c.607G>A LRG_781p1:p.Val203Ile LRG_781t2:c.607G>A LRG_781p2:p.Val203Ile - Protein change
- V203I, V160I, V166I
- Other names
- -
- Canonical SPDI
- NC_000010.11:88941237: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
- Links
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 |
337 | 634 | |
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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, single submitter
|
Jun 26, 2024 | RCV000037197.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 16, 2023 | RCV000645624.8 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 10, 2023 | RCV000726882.7 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2023 | RCV001189711.7 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jul 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000521079.5
First in ClinVar: Mar 08, 2017 Last updated: Jul 22, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient referred for Marfan syndrome, Loeys-Dietz syndrome or TAAD … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient referred for Marfan syndrome, Loeys-Dietz syndrome or TAAD genetic testing; detailed clinical information was not provided (Lerner-Ellis et al., 2014); This variant is associated with the following publications: (PMID: 24793577) (less)
|
|
|
Uncertain significance
(Aug 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001357061.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with isoleucine at codon 203 of the ACTA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces valine with isoleucine at codon 203 of the ACTA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals suspected to be affected with thoracic aortic aneurysm and dissection (PMID: 24793577, 29907982). This variant has been identified in 6/250930 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)
|
|
|
Uncertain Significance
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004840635.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces valine with isoleucine at codon 203 of the ACTA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces valine with isoleucine at codon 203 of the ACTA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals suspected to be affected with thoracic aortic aneurysm and dissection (PMID: 24793577, 29907982). This variant has been identified in 6/250930 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: 4
|
|
|
Uncertain significance
(Jun 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005205341.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: ACTA2 c.607G>A (p.Val203Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: ACTA2 c.607G>A (p.Val203Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250930 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.607G>A has been reported in the literature in at-least one individual affected with Aortopathy (example: Lerner-Ellis_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24793577). ClinVar contains an entry for this variant (Variation ID: 44218). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(Dec 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000703858.2
First in ClinVar: Mar 08, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Uncertain significance
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic aneurysm, familial thoracic 6
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000767374.4
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. This variant disrupts the p.Val203 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been observed in individuals with ACTA2-related conditions (PMID: 29907982), which suggests that this may be a clinically significant amino acid residue. 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: 44218). This missense change has been observed in individuals with thoracic aortic aneurysms and dissections (PMID: 24793577; Invitae). This variant is present in population databases (rs397516684, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 203 of the ACTA2 protein (p.Val203Ile). (less)
|
|
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Uncertain significance
(Nov 11, 2008)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060854.5
First in ClinVar: May 03, 2013 Last updated: Mar 08, 2017 |
Number of individuals with the variant: 1
|
Comment:
Comment:
This missense variant replaces valine with isoleucine at codon 203 of the ACTA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals suspected to be affected with thoracic aortic aneurysm and dissection (PMID: 24793577, 29907982). This variant has been identified in 6/250930 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.
Comment:
This missense variant replaces valine with isoleucine at codon 203 of the ACTA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals suspected to be affected with thoracic aortic aneurysm and dissection (PMID: 24793577, 29907982). This variant has been identified in 6/250930 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.
Comment:
Variant summary: ACTA2 c.607G>A (p.Val203Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250930 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.607G>A has been reported in the literature in at-least one individual affected with Aortopathy (example: Lerner-Ellis_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24793577). ClinVar contains an entry for this variant (Variation ID: 44218). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
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. This variant disrupts the p.Val203 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been observed in individuals with ACTA2-related conditions (PMID: 29907982), which suggests that this may be a clinically significant amino acid residue. 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: 44218). This missense change has been observed in individuals with thoracic aortic aneurysms and dissections (PMID: 24793577; Invitae). This variant is present in population databases (rs397516684, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 203 of the ACTA2 protein (p.Val203Ile).
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. |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient referred for Marfan syndrome, Loeys-Dietz syndrome or TAAD genetic testing; detailed clinical information was not provided (Lerner-Ellis et al., 2014); This variant is associated with the following publications: (PMID: 24793577)
Comment:
This missense variant replaces valine with isoleucine at codon 203 of the ACTA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals suspected to be affected with thoracic aortic aneurysm and dissection (PMID: 24793577, 29907982). This variant has been identified in 6/250930 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.
Comment:
This missense variant replaces valine with isoleucine at codon 203 of the ACTA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals suspected to be affected with thoracic aortic aneurysm and dissection (PMID: 24793577, 29907982). This variant has been identified in 6/250930 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.
Comment:
Variant summary: ACTA2 c.607G>A (p.Val203Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250930 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.607G>A has been reported in the literature in at-least one individual affected with Aortopathy (example: Lerner-Ellis_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24793577). ClinVar contains an entry for this variant (Variation ID: 44218). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
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. This variant disrupts the p.Val203 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been observed in individuals with ACTA2-related conditions (PMID: 29907982), which suggests that this may be a clinically significant amino acid residue. 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: 44218). This missense change has been observed in individuals with thoracic aortic aneurysms and dissections (PMID: 24793577; Invitae). This variant is present in population databases (rs397516684, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 203 of the ACTA2 protein (p.Val203Ile).
Citations for germline classification of this variant
Help| Title | 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 |
| The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). | Lerner-Ellis JP | Molecular genetics and metabolism | 2014 | PMID: 24793577 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACTA2 | - | - | - | - |
Text-mined citations for rs397516684 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.