rs121434526

Variant names:

• chr10-88941794-G-A
• rs121434526
• NM_001613.4:c.445C>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.93

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]

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]

ACMG classification

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	c.445C>T	p.Arg149Cys	missense_variant	Exon 5 of 9	ENST00000224784.10	NP_001604.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32

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: 3 AN: 1459660 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725868

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: 1 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

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

Submissions by phenotype

not provided Pathogenic:4

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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. -

Dec 06, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Nov 07, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 19, 2012

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aortic aneurysm, familial thoracic 6 Pathogenic:2

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 28, 2016

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
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	D
LIST_S2	Uncertain	0.89	D;.;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;.
PrimateAI	Pathogenic	0.92	D
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	D
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

Other links and lift over

dbSNP: rs121434526; hg19: chr10-90701551;