10-88941309-C-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.536G>A(p.Arg179His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ACTA2
NM_001613.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 7.86

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 chr10-88941310-G-A 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, 0.95

PP5

Variant 10-88941309-C-T is Pathogenic according to our data. Variant chr10-88941309-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-88941309-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001613.4 link	c.536G>A	p.Arg179His	missense_variant	Exon 6 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.536G>A	p.Arg179His	missense_variant	Exon 6 of 9	1	NM_001613.4	ENSP00000224784.6		P62736

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multisystemic smooth muscle dysfunction syndrome

Pathogenic:6

Jun 10, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2023

Institute of Human Genetics, Heidelberg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation has been described in the literature as disease-causing and has been identified twice in our laboratory as a de novo mutation. Once in a 9-month-old female with mild delays, hypotonia, microcephaly, iridial dysplasia, mild aortic stenosis, PDA, neurogenic bladder, and loose skin on abdomen. Once in a 3-year-old female with global delays, hypertonia, seizures, structural brain abnormalities, and aorto-pulmonary window. -

Mar 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 14, 2022

Institute of Medical Genetics, University of Zurich

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with familial thoracic aortic aneurysm 6 (MIM#611788), Moyamoya disease 5 (MIM#614042) and multisystemic smooth muscle dysfunction syndrome (MIM#613834) (PMID: 27551047, 28652363). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Actin domain (NCBI). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes to serine and cysteine have been reported in individuals with smooth muscle dysfunction syndrome (ClinVar, PMID: 29300374). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent de novo pathogenic variant in individuals with multisystemic smooth muscle dysfunction syndrome (ClinVar, PMID: 29300374, 31911919). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:3

Jan 13, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R179H pathogenic mutation (also known as c.536G>A), located in coding exon 5 of the ACTA2 gene, results from a G to A substitution at nucleotide position 536. The arginine at codon 179 is replaced by histidine, an amino acid with highly similar properties. This well-characterized mutation has been detected in numerous patients with multisystem smooth muscle dysfunction syndrome (MSMDS), with a likely de novo origin in at least 9 of the individuals (e.g., Milewicz DM et al. Am J Med Genet A. 2010;152A(10):2437-2443; Roder C et al. Eur J Paediatr Neurol. 2011;15(2): 117-122; Munot P et al. Brain. 2012;135:2506-14; Richer J et al. Am J Med Genet A. 2012;158(3): 664-668; Roulez FM et al. J Neuroophthalmol. 2014;34:137-43; Yetman AT et al. Pediatrics. 2015;136:e262-6). The equivalent mutation in zebrafish causes cardiac dysfunction in homozygotes and some heterozygotes, and in vitro functional studies suggest that this mutation causes defects in actin nucleation and polymerization (Bartman T et al. PLoS Biol. 2004;2:E129; Lu H et al. J. Biol. Chem. 2016;291:21729-21739). In addition, two other likely pathogenic alterations, p.R179C and p.R179L, have been described in the same codon (Munot P et al. Brain. 2012;135:2506-14; Meuwissen ME et al. Am. J. Med. Genet. A, 2013 Jun;161A:1376-80). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Sep 28, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg179His variant in ACTA2 gene has been reported in the literature in six i ndividuals with multisystemic smooth muscle dysfunction. Five of these individua ls were found to have a novel syndrome characterized by aortic and cerebrovascul ar disease, fixed dilated pupils, hypotonic bladder, malrotation and hypoperista lsis of the gut, and pulmonary hypertension (Milewicz 2010). The remaining indiv idual was found amongst a cerebrovascular cohort of patients with a diagnosis of Moyamoya Disease (Roder 2011). This particular variant was absent from at least 136 control chromosomes tested (Roder 2011). Heterozygous missense variants in ACTA2 are associated with a variety of cerebrovascular abnormalities including a neurysms and dissections of the thoracic aorta, early onset coronary artery dise ase and strokes, and show extensive familial segregation (Guo 2009). However, in five of six probands the variant was demonstrated to occur de novo (Milewicz 20 10) and in the remaining proband there was no family history of a vascular disor der (Roder 2011). In summary, this variant is highly likely to be pathogenic. -

not provided

Pathogenic:3

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrated this variant results in severe polymerization defects, and smooth muscle myosin moved R179H filaments more slowly than wild-type, even when copolymerized with equimolar amounts of wild-type actin (PMID: 27551047); Not observed 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: 24293535, 24998021, 27567161, 25326635, 32779812, 24621862, 20734336, 22752479, 28343608, 28328125, 25944730, 26637293, 20970362, 22831780, 22302747, 19409525, 25759435, 13129918, 27481187, 29300374, 30300893, 28152038, 29875232, 23613326, 31911919, 32452246, 32369273, 32860008, 33644862, 33199432, 32595813, 34734057, 34732400, 26034244, 22946110, 27551047) -

Aortic aneurysm, familial thoracic 6

Pathogenic:2

Dec 26, 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 histidine, which is basic and polar, at codon 179 of the ACTA2 protein (p.Arg179His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multisystemic smooth muscle dysfunction syndrome (PMID: 20734336, 22302747, 22752479, 22946110, 24293535, 24621862, 24998021, 25944730, 26034244). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29598). 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. -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Moyamoya disease 5

Pathogenic:2

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Connective tissue disorder;CN239849:alterations of great arteries and veins

Pathogenic:1

Jun 09, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ACTA2-related disorder

Pathogenic:1

Mar 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACTA2 c.536G>A variant is predicted to result in the amino acid substitution p.Arg179His. This variant was reported to have occurred de novo in numerous individuals with multisystem smooth muscle dysfunction syndrome (Milewicz et al. 2010. PubMed ID: 20734336; Regalado et al. 2018. PubMed ID: 29300374). Functional studies showed that this variant results in severe polymerization defects (Lu et al. 2016. PubMed ID: 27551047). This variant has not been reported in a large population database, indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.Arg179Ser, p.Arg179Cys, p.Arg179Leu) have been reported to be disease causing (Regalado et al. 2018. PubMed ID: 29300374). Taken together, the c.536G>A (p.Arg179His) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.2

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.85

Sift4G

Benign

0.083

Polyphen

0.089

Vest4

0.93

MutPred

0.84

Gain of catalytic residue at M178 (P = 0.0249);

MVP

0.97

ClinPred

0.99

GERP RS

5.9

Varity_R

0.80

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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