NM_001613.4:c.115C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001613.4(ACTA2):c.115C>T(p.Arg39Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R39H) has been classified as Pathogenic.

Frequency

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

Consequence

ACTA2
NM_001613.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 4.62

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 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-88948815-C-T is described in Lovd as [Pathogenic].

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, 0.949

PP5

Variant 10-88948816-G-A is Pathogenic according to our data. Variant chr10-88948816-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-88948816-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.115C>T	p.Arg39Cys	missense_variant	Exon 2 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.115C>T	p.Arg39Cys	missense_variant	Exon 2 of 9	1	NM_001613.4	ENSP00000224784.6		P62736

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152112

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:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

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:

0.0000943

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACTA2: PM1, PM2, PM5, PS4:Moderate, PP1, PP3 -

Feb 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACTA2 c.115C>T; p.Arg39Cys variant (rs112901682) is reported in multiple individuals with thoracic aortic disorders and shown to segregate with disease in affected family members (Campens 2015, Hoffjan 2011, Kaw 2022, Li 2021, Overwater 2018). This variant is also reported in ClinVar (Variation ID: 65449). This variant is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.853). Additionally, other variants at this codon (p.Arg39Gly, p.Arg39His) are reported in individuals with aortic aneurysm and dissection and are considered to be causative (Hoffjan 2011, Overwater 2018, Regalado 2015). Based on available information, the p.Arg39Cys variant is considered to be pathogenic. References: Campens L et al. Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. Orphanet J Rare Dis. 2015 Feb 3;10:9. PMID: 25644172. Hoffjan S et al. Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. Eur J Hum Genet. 2011 May;19(5):520-4. PMID: 21248741. Kaw A et al. Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome. Am J Med Genet A. 2022 Aug;188(8):2389-2396. PMID: 35567597. Li J et al. Genetic testing and clinical relevance of patients with thoracic aortic aneurysm and dissection in northwestern China. Mol Genet Genomic Med. 2021 Oct;9(10):e1800. PMID: 34498425. Overwater E et al. Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. Hum Mutat. 2018 Sep;39(9):1173-1192. PMID: 29907982. Regalado ES et al. Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. Circ Cardiovasc Genet. 2015 Jun;8(3):457-64. PMID: 25759435. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21733706, 25644172, 25759435, 24243736, 21248741, 21937134, 30030203, 29907982, 31536524, 35567597, 36053285, 34498425) -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:3

Jul 18, 2019

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2014

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R39C variant (also known as c.115C>T), located in coding exon 1 of the ACTA2 gene, results from a C to T substitution at nucleotide position 115. The arginine at codon 39 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with thoracic aortic aneurysm and dissection (TAAD), and co-segregation in affected relatives was reported in two unrelated families (Hoffjan S et al. Eur. J. Hum. Genet., 2011 May;19:520-4; Renard M et al. Int. J. Cardiol., 2013 May;165:314-21; Regalado ES et al. Am. J. Med. Genet. A, 2014 Jan;164A:106-12; Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). Alternate amino acid substitutions at this position, p.R39H and p.R39G, have also been associated with TAAD and vascular disease findings (Guo DC et al. Am J Hum Genet. 2009;84(5):617-27; Regalado ES et al. Circ Cardiovasc Genet. 2015;8(3):457-64). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Aortic aneurysm, familial thoracic 6

Pathogenic:2

Jul 23, 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 39 of the ACTA2 protein (p.Arg39Cys). This variant is present in population databases (rs112901682, gnomAD 0.03%). This missense change has been observed in individuals with aortopathy (PMID: 21248741, 21733706, 21937134, 24243736, 25644172, 25759435). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65449). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

May 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial aortopathy

Pathogenic:1

Jun 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACTA2 c.115C>T (p.Arg39Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251086 control chromosomes. c.115C>T has been reported in the literature in multiple individuals affected with Aortopathy and related conditions (Hoffjan_2011, Ragalado_2014, Renard_2013) and observed to segregate with diseae. Additionally, other missense variants affecting the same codon (e.g. R39H, R39G and R39S) have been classified on the pathogenic spectrum in ClinVar. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21248741, 24243736, 21937134). ClinVar contains an entry for this variant (Variation ID: 65449). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aortic aneurysm, familial thoracic 6;C3151201:Multisystemic smooth muscle dysfunction syndrome;C3279690:Moyamoya disease 5

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PP2+PS4+PP1_Strong -

See cases

Pathogenic:1

Jul 18, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS4,PM1,PM2,PP1,PP3,PP5,BP1 -

ACTA2-related disorder

Pathogenic:1

May 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACTA2 c.115C>T variant is predicted to result in the amino acid substitution p.Arg39Cys. This variant has been reported in multiple individuals with thoracic aortic aneurysms and dissections (TAAD) (Hoffjan et al. 2011. PubMed ID: 21248741; Imai et al. 2011. PubMed ID: 21733706; Campens et al. 2015. PubMed ID: 25644172). Different missense variants affecting the same amino acid codon (p.Arg39His and p.Arg39Gly) have been reported in multiple individuals with TAAD (Guo et al 2009. PubMed ID: 19409525; Yang et al. 2016. PubMed ID: 27611364; Regalado et al. 2015. PubMed ID: 25759435) indicating that this residue is important for ACTA2 function. This variant is reported in 0.029% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.9

M;.;.

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Pathogenic

0.85

Sift4G

Uncertain

0.058

T;.;.

Polyphen

0.040

B;.;.

Vest4

0.83

MutPred

0.86

Loss of methylation at R39 (P = 0.0262);Loss of methylation at R39 (P = 0.0262);Loss of methylation at R39 (P = 0.0262);

MVP

0.99

ClinPred

1.0

GERP RS

5.7

Varity_R

0.88

gMVP

0.95

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