VCV000301509.37 - ClinVar

NM_001613.4(ACTA2):c.390T>C (p.Asn130=)

Germline

Classification

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.

(10)

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.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(1); Likely benign(8)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001613.4(ACTA2):c.390T>C (p.Asn130=)

Variation ID: 301509 Accession: VCV000301509.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.31 10: 88941849 (GRCh38) [ NCBI UCSC ] 10: 90701606 (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	Dec 6, 2016	Oct 20, 2024	Dec 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001613.4:c.390T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001604.1:p.Asn130=	synonymous
NM_001141945.3:c.390T>C	NP_001135417.1:p.Asn130=	synonymous
NM_001320855.2:c.390T>C	NP_001307784.1:p.Asn130=	synonymous
NM_001406462.1:c.390T>C	NP_001393391.1:p.Asn130=	synonymous
NM_001406463.1:c.390T>C	NP_001393392.1:p.Asn130=	synonymous
NM_001406464.1:c.390T>C	NP_001393393.1:p.Asn130=	synonymous
NM_001406466.1:c.279T>C	NP_001393395.1:p.Asn93=	synonymous
NM_001406467.1:c.261T>C	NP_001393396.1:p.Asn87=	synonymous
NM_001406468.1:c.261T>C	NP_001393397.1:p.Asn87=	synonymous
NM_001406469.1:c.261T>C	NP_001393398.1:p.Asn87=	synonymous
NM_001406471.1:c.390T>C	NP_001393400.1:p.Asn130=	synonymous
NC_000010.11:g.88941849A>G
NC_000010.10:g.90701606A>G
NG_011541.1:g.54542T>C
LRG_781:g.54542T>C
LRG_781t1:c.390T>C	LRG_781p1:p.Asn130=
LRG_781t2:c.390T>C	LRG_781p2:p.Asn130=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000010.11:88941848:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA028125 dbSNP: rs141933412 VarSome

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
Gene	OMIM	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	338	635

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.
Multisystemic smooth muscle dysfunction syndrome	Likely benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000299200.7
Familial thoracic aortic aneurysm and aortic dissection	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Dec 25, 2023	RCV000403856.9
not specified	Benign (1)	criteria provided, single submitter	Jun 26, 2015	RCV000443506.3
not provided	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Mar 1, 2021	RCV000586209.25
Connective tissue disorder	Likely benign (1)	criteria provided, single submitter	Jun 1, 2018	RCV000680450.3
Aortic aneurysm, familial thoracic 6	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Oct 9, 2022	RCV001094010.14

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 benign (Jun 13, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697867.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Comment: Variant summary: The ACTA2 c.390T>C (p.Asn130Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a … (more) Variant summary: The ACTA2 c.390T>C (p.Asn130Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant, and 5/5 splicing algorithms predict no significant change to normal splicing. This variant was found in 3/99802 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0000549 (3/54630). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic ACTA2 variant (0.0000175), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Likely Benign until additional information is available. (less)
Benign (Jun 26, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000511958.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Jun 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Connective tissue disorder Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000807823.1 First in ClinVar: Sep 22, 2018 Last updated: Sep 22, 2018
Likely benign (Apr 20, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000913686.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Aortic aneurysm, familial thoracic 6 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000365844.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Likely benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Multisystemic smooth muscle dysfunction syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000365845.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Likely benign (Oct 09, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Aortic aneurysm, familial thoracic 6 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001610139.4 First in ClinVar: May 16, 2021 Last updated: Apr 09, 2023
Likely Benign (Dec 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV004840655.1 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)	Number of individuals with the variant: 9
Likely benign (Dec 25, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005017828.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Mar 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001746025.20 First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1

Comment:

Variant summary: The ACTA2 c.390T>C (p.Asn130Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant, and 5/5 splicing algorithms predict no significant change to normal splicing. This variant was found in 3/99802 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0000549 (3/54630). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic ACTA2 variant (0.0000175), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Likely Benign until additional information is available.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs141933412 ...

These 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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001613.4(ACTA2):c.390T>C (p.Asn130=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs141933412 ...