rs121434526

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_001613.4(ACTA2):c.445C>T(p.Arg149Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ACTA2
NM_001613.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.93

Variant links:

Genes affected

ACTA2 (HGNC:130): (actin alpha 2, smooth muscle) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a smooth muscle actin that is involved in vascular contractility and blood pressure homeostasis. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, and Moyamoya disease, as well as multisystemic smooth muscle dysfunction syndrome. [provided by RefSeq, Sep 2017]

ACTA2 links:

STAMBPL1 (HGNC:24105): (STAM binding protein like 1) Predicted to enable Lys63-specific deubiquitinase activity and thiol-dependent deubiquitinase. Predicted to be involved in protein K63-linked deubiquitination. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

STAMBPL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the ACTA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 4.6117 (above the threshold of 3.09). GenCC associations: The gene is linked to familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome, Moyamoya disease 5.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 10-88941794-G-A is Pathogenic according to our data. Variant chr10-88941794-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-88941794-G-A is described in Lovd as [Likely_pathogenic]. Variant chr10-88941794-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001613.4 link	c.445C>T	p.Arg149Cys	missense_variant	Exon 5 of 9	ENST00000224784.10	NP_001604.1	P62736D2JYH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10 link	c.445C>T	p.Arg149Cys	missense_variant	Exon 5 of 9	1	NM_001613.4	ENSP00000224784.6		P62736

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459660

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725868

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 05, 2017	The patient had genetic testing. The test included sequencing of 10 genes associated with aneurysms and dissections and related conditions: ACTA2, CBS, COL3A1, FBN1, FBN2, MYH11, SLC2A10, SMAD3, TGFBR1 and TGFBR2. Results reported on February 21, 2013 show that a variant was found: p.Arg149Cys (c.445C>T) in the ACTA2 gene The lab classifies this variant as pathogenic. Given significant case and segregation data we consider this variant very likely disease causing and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least seven unrelated cases of hereditary thoracic aortic aneurysm and dissection (including this patient's family). There is strong case and segregation data. Guo, et al, 2008 (PMC: 2680995) reported this variant in four pedigrees of patients with aneurysm/dissection, coronary artery disease and livedo reticularis. This is the most common variant in their cohort of patients with ACTA2 variants, 45 out of 134 individuals with ACTA2 variants (33%). Of the 45 individuals from their cohort, 24 had TAAD and 12 had early onset coronary artery disease. Morisaki, et al, 2009 (PMID: 19639654) reported this variant in a proband who had a positive family history of aortic dissection and iris folliculi. She had been an amateur tennis player in her teens. She had an uneventful delivery of a healthy child 4 years prior to referral. At age 31 Y she experienced an acute Stanford type B dissection during spontaneous vaginal delivery of her second child at 40 weeks. She was treated conservatively with antihypertensive therapy and three weeks later she had aggravation of the dissection and underwent and endovascular repair with a tube stent graft. The patient had livedo reticularis on both legs and iris folliculi bilaterally. Her brother had a Stanford type A aortic dissection at 28 Y and iris folliculi but no livedo reticularis. Disabella, et al, 2011 (PMID: 21212136) reported this variant in a family with three affected individuals. One, a 62 Y female with a pre-op AR of 4.8 cm underwent a Tirone-David replacement after having a type A dissection and borderline hypertension. 38 Y female had a pre-op AR of 4.5 cm and A type a dissection during pregnancy at 33 Y and second type b dissection at 35 Y. She had coronary calcification. A 36 Y M had an aortic root of 3.8 cm (z-score: 4.27), a 28 Y male had an aortic root of 4.1 cm (z-score of 4.49 cm). A 7 Y male had an aortic root of 2.04 (z-score: 1.42). Ambry Genetics reports this variant in one of their patients with TAAD. They did not provide phenotypic details. The variant occurs within the hydrophobic cleft between subdomains 1 and 3 and the Cys substitution is expected to impede the actin-ABP interaction as well as actin-actin contacts. of the protein, as does R118 variants which also predispose to early onset CAD. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar: 0.761). The Arg at codon 149 is conserved across species, as are neighboring amino acids, and much of the ACTA2 gene. Another variant has been reported in association with disease at this codon, p.R149L which had multiple affected individuals with aortic disease, premature CAD and premature stroke. There are seven individuals with missense variation at codon 149 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >125,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Two individuals have p.R149C and five individuals have p.R149H. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2024	Published functional studies in mice demonstrate a damaging effect through decreased force generation of aortic rings, and increased aortic wall thickness (PMID: 34600884); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 36938085, 36053285, 34498425, 29907982, 19639654, 19409525, 19778989, 21212136, 24243736, 25644172, 24020716, 29055370, 31911781, 32154576, 17994018, 34600884) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 02, 2024	The p.R149C pathogenic mutation (also known as c.445C>T), located in coding exon 4 of the ACTA2 gene, results from a C to T substitution at nucleotide position 445. The arginine at codon 149 is replaced by cysteine, an amino acid with highly dissimilar properties. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant has been detected in individuals with features consistent with thoracic aortic aneurysm and dissection (TAAD) or other ACTA2-related vascular phenotypes, and has been reported to segregate with disease features in families (Guo DC et al. Nat Genet. 2007;39(12):1488-1493; Guo DC et al. Am J Hum Genet. 2009;84(5):617-627; Morisaki H et al. Hum Mutat. 2009;30(10):4106-1411). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 19, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 07, 2023	The c.445C>T (p.Arg149Cys) variant of the ACTA2 gene has been observed in individuals with thoracic aortic aneurysms and dissections, premature coronary artery disease, premature stroke, and livedo reticularis (PMID: 17994018, 19409525, 21212136, 21248741, 24020716, 25644172). It has also been observed to segregate with disease in related individuals (PMID: 17994018, 19409525, 21212136). This variant is rare in the general population according to gnomAD (1/278732). Computational evidence supports a deleterious effect on the gene or gene product. Therefore, the c.445C>T (p.Arg149Cys) variant of the ACTA2 gene is classified as pathogenic. -

Aortic aneurysm, familial thoracic 6

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2024	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTA2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Aortic aneurysm, familial thoracic 2

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Mar 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.;.

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.3

D;D;D

REVEL

Pathogenic

0.98

Sift4G

Uncertain

0.0090

D;.;.

Polyphen

1.0

D;.;.

Vest4

0.97

MutPred

0.89

Loss of methylation at R149 (P = 0.0106);Loss of methylation at R149 (P = 0.0106);Loss of methylation at R149 (P = 0.0106);

MVP

0.99

ClinPred

1.0

GERP RS

5.5

Varity_R

0.88

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over