NM_001613.4(ACTA2):c.720G>C (p.Lys240Asn) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Apr 20, 2020
Review status:: criteria provided, conflicting classifications

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:: RCV000150127.12

Allele description [Variation Report for NM_001613.4(ACTA2):c.720G>C (p.Lys240Asn)]

NM_001613.4(ACTA2):c.720G>C (p.Lys240Asn)

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.720G>C (p.Lys240Asn)

HGVS:

NC_000010.11:g.88939595C>G
NG_011541.1:g.56796G>C
NM_001141945.3:c.720G>C
NM_001320855.2:c.720G>C
NM_001406462.1:c.720G>C
NM_001406463.1:c.720G>C
NM_001406464.1:c.720G>C
NM_001406466.1:c.609G>C
NM_001406467.1:c.591G>C
NM_001406468.1:c.591G>C
NM_001406469.1:c.591G>C
NM_001613.4:c.720G>CMANE SELECT
NP_001135417.1:p.Lys240Asn
NP_001135417.1:p.Lys240Asn
NP_001135417.1:p.Lys240Asn
NP_001307784.1:p.Lys240Asn
NP_001307784.1:p.Lys240Asn
NP_001393391.1:p.Lys240Asn
NP_001393392.1:p.Lys240Asn
NP_001393393.1:p.Lys240Asn
NP_001393395.1:p.Lys203Asn
NP_001393396.1:p.Lys197Asn
NP_001393397.1:p.Lys197Asn
NP_001393398.1:p.Lys197Asn
NP_001604.1:p.Lys240Asn
NP_001604.1:p.Lys240Asn
LRG_781t1:c.720G>C
LRG_781t2:c.720G>C
LRG_781:g.56796G>C
LRG_781p1:p.Lys240Asn
LRG_781p2:p.Lys240Asn
NC_000010.10:g.90699352C>G
NM_001141945.1:c.720G>C
NM_001141945.2:c.720G>C
NM_001320855.1:c.720G>C
NM_001613.2:c.720G>C
NR_125373.1:n.1664C>G

Protein change:

K197N

Links:

dbSNP: rs727502878

NCBI 1000 Genomes Browser:

rs727502878

Molecular consequence:

NM_001141945.3:c.720G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001320855.2:c.720G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406462.1:c.720G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406463.1:c.720G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406464.1:c.720G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406466.1:c.609G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406467.1:c.591G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406468.1:c.591G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406469.1:c.591G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001613.4:c.720G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_125373.1:n.1664C>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
SCV000196973	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Sep 20, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002042324	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 20, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000196973

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Sep 20, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002042324

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 20, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000196973.4

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

Description

The p.Lys240Asn variant in ACTA2 has been identified by our laboratory in 1 indi vidual with familial thoracic aortic aneurysms/dissections (TAAD) and segregated with disease in at least 5 affected relatives including 3 obligate carriers (Pr evention Genetics and LMM, unpublished data). It was absent from large populatio n studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are r equired to fully establish its clinical significance, the p.Lys240Asn variant is likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	1	not provided

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV002042324.1

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

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

Last Updated: May 3, 2025

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