Submissions for variant NM_001613.4(ACTA2):c.536G>A (p.Arg179His)

dbSNP: rs387906592

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000181023	SCV000060853	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2011-09-28	criteria provided, single submitter	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.
GeneDx	RCV000211886	SCV000233298	pathogenic	not provided	2021-03-31	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); 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 (Lu et al., 2006); 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, 22946110, 24621862, 20734336, 22752479, 26034244, 28343608, 28328125, 25944730, 27551047, 26637293, 20970362, 22831780, 22302747, 19409525, 25759435, 13129918, 27481187, 29300374, 30300893, 28152038, 29875232, 23613326, 31911919, 32452246, 32369273)
Invitae	RCV000228180	SCV000287174	pathogenic	Aortic aneurysm, familial thoracic 6	2023-10-30	criteria provided, single submitter	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). 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.
Ambry Genetics	RCV000181023	SCV000318100	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2017-03-16	criteria provided, single submitter	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.
Baylor Genetics	RCV000022437	SCV000807328	pathogenic	Multisystemic smooth muscle dysfunction syndrome	2017-09-01	criteria provided, single submitter	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.
Fulgent Genetics, Fulgent Genetics	RCV000763224	SCV000893851	pathogenic	Aortic aneurysm, familial thoracic 6; Multisystemic smooth muscle dysfunction syndrome; Moyamoya disease 5	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000022437	SCV001149664	pathogenic	Multisystemic smooth muscle dysfunction syndrome	2020-06-10	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000022438	SCV001426448	pathogenic	Moyamoya disease 5		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000181023	SCV002042323	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-01-13	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000022437	SCV002557770	pathogenic	Multisystemic smooth muscle dysfunction syndrome	2022-02-02	criteria provided, single submitter	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
Institute of Medical Genetics, University of Zurich	RCV000022437	SCV002569049	pathogenic	Multisystemic smooth muscle dysfunction syndrome	2022-05-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532396	SCV004719068	pathogenic	ACTA2-related disorder	2023-12-11	criteria provided, single submitter	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000228180	SCV004807971	pathogenic	Aortic aneurysm, familial thoracic 6	2024-03-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Heidelberg University	RCV000022437	SCV004814201	pathogenic	Multisystemic smooth muscle dysfunction syndrome	2023-11-03	criteria provided, single submitter	clinical testing
OMIM	RCV000022437	SCV000043726	pathogenic	Multisystemic smooth muscle dysfunction syndrome	2011-03-01	no assertion criteria provided	literature only
OMIM	RCV000022438	SCV000043727	pathogenic	Moyamoya disease 5	2011-03-01	no assertion criteria provided	literature only
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415107	SCV000492539	pathogenic	alterations of great arteries and veins; Connective tissue disorder	2016-06-09	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000211886	SCV001807059	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000211886	SCV001973424	pathogenic	not provided		no assertion criteria provided	clinical testing