VCV000918694.11 - ClinVar

NM_001613.4(ACTA2):c.1109C>G (p.Ser370Cys)

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.

(5)

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

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.1109C>G (p.Ser370Cys)

Variation ID: 918694 Accession: VCV000918694.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.31 10: 88935248 (GRCh38) [ NCBI UCSC ] 10: 90695005 (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	Jun 22, 2020	May 1, 2024	Jan 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001613.4:c.1109C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001604.1:p.Ser370Cys	missense
NM_001141945.3:c.1109C>G	NP_001135417.1:p.Ser370Cys	missense
NM_001320855.2:c.1109C>G	NP_001307784.1:p.Ser370Cys	missense
NM_001406462.1:c.1109C>G	NP_001393391.1:p.Ser370Cys	missense
NM_001406463.1:c.1109C>G	NP_001393392.1:p.Ser370Cys	missense
NM_001406464.1:c.1109C>G	NP_001393393.1:p.Ser370Cys	missense
NM_001406466.1:c.998C>G	NP_001393395.1:p.Ser333Cys	missense
NM_001406467.1:c.980C>G	NP_001393396.1:p.Ser327Cys	missense
NM_001406468.1:c.980C>G	NP_001393397.1:p.Ser327Cys	missense
NM_001406469.1:c.980C>G	NP_001393398.1:p.Ser327Cys	missense
NM_001406471.1:c.917C>G	NP_001393400.1:p.Ser306Cys	missense
NR_125373.1:n.873G>C		non-coding transcript variant
NC_000010.11:g.88935248G>C
NC_000010.10:g.90695005G>C
NG_011541.1:g.61143C>G
LRG_781:g.61143C>G
LRG_781t1:c.1109C>G	LRG_781p1:p.Ser370Cys
LRG_781t2:c.1109C>G	LRG_781p2:p.Ser370Cys

... more HGVS ... less HGVS

Protein change

S370C, S306C, S327C, S333C

Other names

Canonical SPDI

NC_000010.11:88935247:G:C

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) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs749867078 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
ACTA2-AS1	-	-	-	GRCh38	-	245

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.
Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Jan 11, 2024	RCV001176424.11
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 25, 2021	RCV002223993.3

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.
Uncertain significance (Aug 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501941.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Number of individuals with the variant: 1 Secondary finding: no
Uncertain significance (May 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) 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 Accession: SCV003838449.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Uncertain significance (Dec 05, 2023)	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: SCV001340401.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Comment: This missense variant replaces serine with cysteine at codon 370 of the ACTA2 protein. Computational prediction tools and conservation analyses suggest that this variant may … (more) This missense variant replaces serine with cysteine at codon 370 of the ACTA2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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 (Jan 11, 2024)	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: SCV004840590.1 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 serine with cysteine at codon 370 of the ACTA2 protein. Computational prediction tools and conservation analyses suggest that this variant may … (more) This missense variant replaces serine with cysteine at codon 370 of the ACTA2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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: 3
Uncertain significance (Oct 27, 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: SCV005018244.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The p.S370C variant (also known as c.1109C>G), located in coding exon 8 of the ACTA2 gene, results from a C to G substitution at nucleotide … (more) The p.S370C variant (also known as c.1109C>G), located in coding exon 8 of the ACTA2 gene, results from a C to G substitution at nucleotide position 1109. The serine at codon 370 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This missense variant replaces serine with cysteine at codon 370 of the ACTA2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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:

The p.S370C variant (also known as c.1109C>G), located in coding exon 8 of the ACTA2 gene, results from a C to G substitution at nucleotide position 1109. The serine at codon 370 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868

Text-mined citations for rs749867078 ...

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 May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001613.4(ACTA2):c.1109C>G (p.Ser370Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs749867078 ...