rs794728021

chr10-88948815-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 NM_001613.4(ACTA2):c.116G>A(p.Arg39His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R39C) has been classified 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:8
• 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]

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 chr10-88948816-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.
• PP2: Missense variant where missense usually causes diseases, ACTA2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 10-88948815-C-T is Pathogenic according to our data. Variant chr10-88948815-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-88948815-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA2	NM_001613.4	c.116G>A	p.Arg39His	missense_variant	2/9	ENST00000224784.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA2	ENST00000224784.10	c.116G>A	p.Arg39His	missense_variant	2/9	1	NM_001613.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 04, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 15, 2020	The p.R39H variant (also known as c.116G>A), located in coding exon 1 of the ACTA2 gene, results from a G to A substitution at nucleotide position 116. The arginine at codon 39 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in multiple unrelated individuals with ACTA2-related vascular phenotypes (Guo DC et al, Am. J. Hum. Genet. 2009 May; 84(5):617-27; Regalado ES et al, Am. J. Med. Genet. A 2014 Jan; 164A(1):106-12; Yang H et al. Sci Rep, 2016 09;6:33002; Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192; GeneDx pers. comm.; Invitae pers. comm.). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jan 05, 2024	This sequence change in ACTA2 is predicted to replace arginine with histidine at codon 39, p.(Arg39His). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the SD2 domain (PMID: 19409525). Three alternate residues at position Arg39 (R39) have been previously reported as likely pathogenic/pathogenic suggesting the residue is critical to protein function (ClinVar ID = 199665;1066384; 65449). There is a small physicochemical difference between arginine and histidine. ACTA2, in which the variant was identified, is a gene with a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least four unrelated individuals with thoracic aortic aneurysm with dissection (TAAD) with/without a history of stroke (PMID:19409525, 27611364, 29907982). The variant has been reported to segregate with TAAD in affected family members from two unrelated families (PMID: 19409525). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.867). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PM2_Supporting, PP1_Strong, PP2, PP3, PS4_Supporting -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 17, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2022	Has been reported in association with aortic dissection or aortopathy (Regalado et al., 2014; Yang et al., 2016); 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: 19409525, 21248741, 27611364, 26934405, 24243736, 26153420, 20689142, 29907982, 21937134, 21212136) -

Aortic aneurysm, familial thoracic 6 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 13, 2023	Criteria applied: PM5_STR,PS4_MOD,PM2_SUP,PP2,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 39 of the ACTA2 protein (p.Arg39His). This missense change has been observed in individuals with aortic dissections (PMID: 19409525, 27611364; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg39 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21248741, 21733706, 21937134, 24243736, 25644172, 25759435). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 199666). -

Familial aortopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Sep 24, 2018

Variant summary: ACTA2 c.116G>A (p.Arg39His) results in a non-conservative amino acid change affecting a highly conserved residue located in the subdomain 2 (SD2) of the encoded protein sequence, whose dynamics are essential for ATP hydrolysis (Guo 2009). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121750 control chromosomes (ExAC and publication data). The variant has been reported in two unrelated families with multiple affected family members who had TAAD, Type A or Type B aortic dissection, coronary artery disease, patent ductus arteriosus, and/or stroke (Guo 2009), however, only ACTA2 was screened for in these families, and one unaffected individual, above the average age of onset for aortopathy (20 y/o), from each family was identified as a carrier of R39H. After contacting the corresponding author for this paper, they indicated that there has been no addtional follow-up with the discordant members from the two families carrying the variant of interest since the publication. The variant was also reported recently in a patient with aortic dissection, and in his father with aortic aneurism (Overwater 2018). In addition, the variant was identified in an internal specimen (18 month old female whose phenotype is unknown), whose mother was indicated to be a carrier of the variant of interest and presented with stroke, left MCA infarcts, history of hyperplastic vascular myopathy and aneurysms. A missense variant at the same position, R39C, was reported in patients with aortic aneurysm or mild aortic dilatation and insufficiency, indicating that R39 is a critical amino acid and changes at this position could affect function of ACTA2 (Hoffjan 2011). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (classifying the variant as Pathogenic, Likely pathogenic or VUS). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.3	N;D;D
REVEL	Pathogenic	0.87
Sift4G	Benign	0.10	T;.;.
Polyphen		0.017	B;.;.
Vest4		0.72
MutPred		0.89		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		0.99	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.88

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: rs794728021; hg19: chr10-90708572; COSMIC: COSV56515596;