rs397516685

Positions:

• chr10-88939680-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001613.4(ACTA2):​c.635G>A​(p.Arg212Gln) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.91

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]

ACTA2-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.933
• PP5: Variant 10-88939680-C-T is Pathogenic according to our data. Variant chr10-88939680-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-88939680-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.635G>A	p.Arg212Gln	missense_variant	7/9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.635G>A	p.Arg212Gln	missense_variant	7/9	1	NM_001613.4	ENSP00000224784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 18, 2020	The p.Arg212Gln variant in ACTA2 has been reported in at least 4 individuals (1 de novo, paternity confirmed) with familial thoracic aortic aneurysm disease (TAAD) and segregated with TAAD in 6 affected individuals from 1 family as well as with 1 sister with premature stroke and 1 mother with CAD from another family (Guo 2009 PMID: 19409525, Morisaki 2009 PMID: 19639654, Fang 2017 PMID: 28855619). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial TAAD. ACMG/AMP Criteria applied: PS2, PP1_Strong, PM2, PP3, PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 24, 2019	Variant summary: ACTA2 c.635G>A (p.Arg212Gln) results in a 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 250572 control chromosomes (gnomAD). c.635G>A has been reported in the literature in multiple individuals affected with Thoracic Aortic Aneurysms and Dissections, premature stroke, and CAD (Morisaki_2009, Guo_2009, Fang_2017). 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. Four ClinVar submissions (evaluation after 2014) cites the variant once as likely pathogenic and three times as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 30, 2016	The p.R212Q pathogenic mutation (also known as c.635G>A), located in coding exon 6 of the ACTA2 gene, results from a G to A substitution at nucleotide position 635. The arginine at codon 212 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been described in families with thoracic aortic aneurysms and dissections (TAAD), co-segregating with disease in multiple relatives (Morisaki H et al. Hum Mutat. 2009;30:1406-11). In one study, this alteration was confirmed to be a de novo occurrence in a patient with premature stroke prior to presenting with acute aortic dissection (Guo DC et al. Am J Hum Genet. 2009;84:617-27). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Aortic aneurysm, familial thoracic 6 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Sep 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 212 of the ACTA2 protein (p.Arg212Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thoracic aortic disease (PMID: 19409525, 19639654). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44219). 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, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

ACTA2-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 03, 2024	The ACTA2 c.635G>A variant is predicted to result in the amino acid substitution p.Arg212Gln. This variant has been reported to segregate with disease in families with thoracic aortic aneurysm and dissection or related conditions (Guo et al. 2009. PubMed ID: 19409525; Morisaki et al. 2009. PubMed ID: 19639654; Regalado et al. 2015. PubMed ID: 25759435). In one individual, this variant was reported to occur de novo (Guo et al. 2009. PubMed ID: 19409525). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 22, 2018	The ACTA2 c.635G>A (p.Arg212Gln) missense variant has been reported in at least five studies in which it is found in at least seven individuals including in a heterozygous state in at least four individuals with thoracic aortic aneurysms and aortic dissections, two with annuloaortic ectasia, and one with Moyamoya disease (Guo et al. 2009; Morisaki et al. 2009; Regalado et al. 2015; Fang et al. 2017; Volozonoka et al. 2018). The p.Arg212Gln variant was shown to segregate with disease in three different families including one family where the p.Arg212Gln variant was observed de novo (paternity confirmed) and two other families where the p.Arg212Gln was detected in four other affected family members and absent in five healthy family members over at least two generations (Guo et al. 2009; Morisaki et al. 2009). The p.Arg212Gln variant was absent from 382 controls and is not found in the 1000 Genomes project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database, in a region with good sequence coverage, and hence is presumed to be rare. Based on the collective evidence, the p.Arg212Gln variant is classified as pathogenic for ACTA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2024	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: 21248741, 33057194, 35982159, 34758253, 25759435, 25910212, 19409525, 19639654, 28855619, 24793577, 29687370, 30990720, 34422331, 33824467) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 15, 2018	- -

Isolated thoracic aortic aneurysm Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Vascular Biology, Beijing Anzhen Hospital

Sep 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.91
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.69		Gain of ubiquitination at K217 (P = 0.0635);
MVP		0.97
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.79
gMVP		0.93

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: rs397516685; hg19: chr10-90699437;