NM_001613.4(ACTA2):c.678A>C (p.Glu226Asp) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 23, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004009499.2

Allele description [Variation Report for NM_001613.4(ACTA2):c.678A>C (p.Glu226Asp)]

NM_001613.4(ACTA2):c.678A>C (p.Glu226Asp)

Genes:

ACTA2-AS1:ACTA2 antisense RNA 1 [Gene - HGNC]
ACTA2:actin alpha 2, smooth muscle [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_001613.4(ACTA2):c.678A>C (p.Glu226Asp)

HGVS:

NC_000010.11:g.88939637T>G
NG_011541.1:g.56754A>C
NM_001141945.3:c.678A>C
NM_001320855.2:c.678A>C
NM_001406462.1:c.678A>C
NM_001406463.1:c.678A>C
NM_001406464.1:c.678A>C
NM_001406466.1:c.567A>C
NM_001406467.1:c.549A>C
NM_001406468.1:c.549A>C
NM_001406469.1:c.549A>C
NM_001613.4:c.678A>CMANE SELECT
NP_001135417.1:p.Glu226Asp
NP_001135417.1:p.Glu226Asp
NP_001135417.1:p.Glu226Asp
NP_001307784.1:p.Glu226Asp
NP_001307784.1:p.Glu226Asp
NP_001393391.1:p.Glu226Asp
NP_001393392.1:p.Glu226Asp
NP_001393393.1:p.Glu226Asp
NP_001393395.1:p.Glu189Asp
NP_001393396.1:p.Glu183Asp
NP_001393397.1:p.Glu183Asp
NP_001393398.1:p.Glu183Asp
NP_001604.1:p.Glu226Asp
NP_001604.1:p.Glu226Asp
LRG_781t1:c.678A>C
LRG_781t2:c.678A>C
LRG_781:g.56754A>C
LRG_781p1:p.Glu226Asp
LRG_781p2:p.Glu226Asp
NC_000010.10:g.90699394T>G
NM_001141945.1:c.678A>C
NM_001141945.2:c.678A>C
NM_001320855.1:c.678A>C
NM_001613.2:c.678A>C
NR_125373.1:n.1706T>G

Protein change:

E183D

Molecular consequence:

NM_001141945.3:c.678A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001320855.2:c.678A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406462.1:c.678A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406463.1:c.678A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406464.1:c.678A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406466.1:c.567A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406467.1:c.549A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406468.1:c.549A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406469.1:c.549A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001613.4:c.678A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_125373.1:n.1706T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004840627	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28659821, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004840627

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 23, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor.

Gillis E, Kumar AA, Luyckx I, Preuss C, Cannaerts E, van de Beek G, Wieschendorf B, Alaerts M, Bolar N, Vandeweyer G, Meester J, Wünnemann F, Gould RA, Zhurayev R, Zerbino D, Mohamed SA, Mital S, Mertens L, Björck HM, Franco-Cereceda A, McCallion AS, Van Laer L, et al.

Front Physiol. 2017;8:400. doi: 10.3389/fphys.2017.00400. Erratum in: Front Physiol. 2017 Sep 25;8:730.

PubMed [citation]

PMID:: 28659821
PMCID:: PMC5469151

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004840627.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces glutamic acid with aspartic acid at codon 226 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 an individual affected with thoracic aortic aneurysm and aortic dissection and/or bicuspid aortic valve (PMID: 28659821). This variant has been identified in 1/250888 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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