chr10-88941309-C-T

Position:

• chr10-88941309-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000224784.10(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. R179L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA2 ENST00000224784.10 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 7.86

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 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 ClinVar as [Pathogenic]. Clinvar id is 265026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTA2. . Trascript score misZ 4.6117 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.536G>A	p.Arg179His	missense_variant	6/9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.536G>A	p.Arg179His	missense_variant	6/9	1	NM_001613.4	ENSP00000224784	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multisystemic smooth muscle dysfunction syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	Nov 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics, University of Zurich	May 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 10, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2011	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 13, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 16, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 28, 2011	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

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Aortic aneurysm, familial thoracic 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2023	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). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

Moyamoya disease 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2011	- -

Connective tissue disorder;CN239849:alterations of great arteries and veins Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 09, 2016

- -

Aortic aneurysm, familial thoracic 6;C3151201:Multisystemic smooth muscle dysfunction syndrome;C3279690:Moyamoya disease 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

ACTA2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2024

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	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.85
Sift4G	Benign	0.083	T
Polyphen		0.089	B
Vest4		0.93
MutPred		0.84		Gain of catalytic residue at M178 (P = 0.0249);
MVP		0.97
ClinPred		0.99	D
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

Other links and lift over

dbSNP: rs387906592; hg19: chr10-90701066;