NM_001613.4(ACTA2):c.369+1G>C AND Aortic aneurysm, familial thoracic 6

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 23, 2022
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:: RCV002876823.2

Allele description [Variation Report for NM_001613.4(ACTA2):c.369+1G>C]

NM_001613.4(ACTA2):c.369+1G>C

Gene:

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.369+1G>C

HGVS:

NC_000010.11:g.88943796C>G
NG_011541.1:g.52595G>C
NM_001141945.3:c.369+1G>C
NM_001320855.2:c.369+1G>C
NM_001406462.1:c.369+1G>C
NM_001406463.1:c.369+1G>C
NM_001406464.1:c.369+1G>C
NM_001406466.1:c.259-1927G>C
NM_001406467.1:c.240+1G>C
NM_001406468.1:c.240+1G>C
NM_001406469.1:c.240+1G>C
NM_001406471.1:c.369+1G>C
NM_001613.4:c.369+1G>CMANE SELECT
LRG_781:g.52595G>C
NC_000010.10:g.90703553C>G

Molecular consequence:

NM_001406466.1:c.259-1927G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001141945.3:c.369+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001320855.2:c.369+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406462.1:c.369+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406463.1:c.369+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406464.1:c.369+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406467.1:c.240+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406468.1:c.240+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406469.1:c.240+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406471.1:c.369+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001613.4:c.369+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Aortic aneurysm, familial thoracic 6 (AAT6)
Synonyms:: FAMILIAL THORACIC AORTIC ANEURYSM WITH LIVEDO RETICULARIS AND IRIS FLOCCULI
Identifiers:: MONDO: MONDO:0012730; MedGen: C2673186; OMIM: 611788

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003236380	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 23, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21212136, 16199547, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003236380

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 23, 2022)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2).

Disabella E, Grasso M, Gambarin FI, Narula N, Dore R, Favalli V, Serio A, Antoniazzi E, Mosconi M, Pasotti M, Odero A, Arbustini E.

Heart. 2011 Feb;97(4):321-6. doi: 10.1136/hrt.2010.204388. Epub 2011 Jan 6.

PubMed [citation]

PMID:: 21212136

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003236380.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with thoracic aortic aneurysm and dissection (PMID: 21212136). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the ACTA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ACTA2 cause disease.

#	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: Feb 20, 2024

ClinVar

Relating variation to medicine