NM_001613.4(ACTA2):c.445C>T (p.Arg149Cys) AND Aortic aneurysm, familial thoracic 6

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 18, 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:: RCV000019938.48

Allele description [Variation Report for NM_001613.4(ACTA2):c.445C>T (p.Arg149Cys)]

NM_001613.4(ACTA2):c.445C>T (p.Arg149Cys)

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.445C>T (p.Arg149Cys)

HGVS:

NC_000010.11:g.88941794G>A
NG_011541.1:g.54597C>T
NM_001141945.3:c.445C>T
NM_001320855.2:c.445C>T
NM_001406462.1:c.445C>T
NM_001406463.1:c.445C>T
NM_001406464.1:c.445C>T
NM_001406466.1:c.334C>T
NM_001406467.1:c.316C>T
NM_001406468.1:c.316C>T
NM_001406469.1:c.316C>T
NM_001406471.1:c.445C>T
NM_001613.4:c.445C>TMANE SELECT
NP_001135417.1:p.Arg149Cys
NP_001135417.1:p.Arg149Cys
NP_001135417.1:p.Arg149Cys
NP_001307784.1:p.Arg149Cys
NP_001307784.1:p.Arg149Cys
NP_001393391.1:p.Arg149Cys
NP_001393392.1:p.Arg149Cys
NP_001393393.1:p.Arg149Cys
NP_001393395.1:p.Arg112Cys
NP_001393396.1:p.Arg106Cys
NP_001393397.1:p.Arg106Cys
NP_001393398.1:p.Arg106Cys
NP_001393400.1:p.Arg149Cys
NP_001604.1:p.Arg149Cys
NP_001604.1:p.Arg149Cys
LRG_781t1:c.445C>T
LRG_781t2:c.445C>T
LRG_781:g.54597C>T
LRG_781p1:p.Arg149Cys
LRG_781p2:p.Arg149Cys
NC_000010.10:g.90701551G>A
NM_001141945.1:c.445C>T
NM_001141945.2:c.445C>T
NM_001320855.1:c.445C>T
NM_001613.2:c.445C>T
NM_001613.3:c.445C>T
P62736:p.Arg149Cys

Protein change:

R106C; ARG149CYS

Links:

UniProtKB: P62736#VAR_045918; OMIM: 102620.0001; dbSNP: rs121434526

NCBI 1000 Genomes Browser:

rs121434526

Molecular consequence:

NM_001141945.3:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320855.2:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406462.1:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406463.1:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406464.1:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406466.1:c.334C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406467.1:c.316C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406468.1:c.316C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406469.1:c.316C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406471.1:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001613.4:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000040236	OMIM	no assertion criteria provided	Pathogenic (May 1, 2009)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17994018, 19409525
SCV000541639	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 18, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19409525, 21212136, 21248741, 24020716, 25644172, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000040236

OMIM

no assertion criteria provided

Pathogenic
(May 1, 2009)

germline

literature only

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

SCV000541639

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 18, 2023)

germline

clinical testing

PubMed (6)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.

Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, Bourgeois S, Estrera AL, Safi HJ, Sparks E, Amor D, Ades L, McConnell V, Willoughby CE, Abuelo D, Willing M, Lewis RA, Kim DH, Scherer S, Tung PP, Ahn C, Buja LM, et al.

Nat Genet. 2007 Dec;39(12):1488-93. Epub 2007 Nov 11. Erratum in: Nat Genet. 2008 Feb;40(2):255.

PubMed [citation]

PMID:: 17994018

Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease.

Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N, Johnson RJ, Kim DH, Pannu H, Willing MC, Sparks E, Pyeritz RE, Singh MN, Dalman RL, Grotta JC, Marian AJ, Boerwinkle EA, Frazier LQ, LeMaire SA, Coselli JS, Estrera AL, Safi HJ, Veeraraghavan S, et al.

Am J Hum Genet. 2009 May;84(5):617-27. doi: 10.1016/j.ajhg.2009.04.007. Epub 2009 Apr 30.

PubMed [citation]

PMID:: 19409525
PMCID:: PMC2680995

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000040236.4

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

Description

In a large family in which thoracic aortic aneurysm with dissection segregated with reduced penetrance (AAT6; 611788), Guo et al. (2007) found a heterozygous 492C-T transition in exon 5 of the ACTA2 gene that caused an arg149-to-cys (R149C) amino acid substitution. In further studies, 4 additional families with the ACTA2 mutation were found; however, each family had a unique haplotype, implying that the mutations arose de novo in multiple families. Livedo reticularis and iris flocculi were found together or separately in some of these families.

Guo et al. (2009) analyzed 45 individuals with the R149C mutation and found that, in addition to the already established predisposition to TAAD, this mutation led to coronary artery disease (24 mutation carriers with TAAD, 12 with coronary artery disease).

#	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		not provided	not provided	not provided	not provided

From Invitae, SCV000541639.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 149 of the ACTA2 protein (p.Arg149Cys). This variant is present in population databases (rs121434526, gnomAD 0.0008%). This missense change has been observed in individuals with thoracic aortic aneurysms and dissections (PMID: 19409525, 21212136, 21248741, 24020716, 25644172). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18276). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTA2 protein function. For these reasons, this variant has been classified as Pathogenic.

#	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: Apr 20, 2024

ClinVar

Relating variation to medicine