rs886039303
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001613.4(ACTA2):c.535C>T(p.Arg179Cys) variant causes a missense change. 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
NM_001613.4 missense
NM_001613.4 missense
Scores
14
2
2
Clinical Significance
Conservation
PhyloP100: 5.56
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]
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 chr10-88941309-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.
PP2
?
Missense variant where missense usually causes diseases, ACTA2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
?
Variant 10-88941310-G-A is Pathogenic according to our data. 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. Variant chr10-88941310-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA2 | NM_001613.4 | c.535C>T | p.Arg179Cys | missense_variant | 6/9 | ENST00000224784.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA2 | ENST00000224784.10 | c.535C>T | p.Arg179Cys | missense_variant | 6/9 | 1 | NM_001613.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multisystemic smooth muscle dysfunction syndrome Pathogenic:3
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 cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Actin domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Alternative changes to leucine, histidine and serine 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 pathogenic variant in individuals with multisystemic smooth muscle dysfunction syndrome (ClinVar, PMID: 23613326, PMID: 29300374). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Nov 21, 2019 | The p.Arg179Cys variant has been previously reported as de novo in patients with multisystemic smooth muscle dysfunction syndrome (MSMDS) disorder (PMID: 23613326, 27567161, 27244053, 27481187, 29875232). Multiple missense alterations at the same amino acid residue, including the recurrent p.Arg179His substitution, have been reported in association with MSMDS (PMID: 22831780, 24621862, 20734336, 26034244, 22752479, 24998021, 22946110, 24293535). Functional in-vitro studies variant using a baculovirus/insect cell system showed the p.Arg179Cys variant severely affects smooth muscle alpha-actin functions (PMID: 26153420). The p.Arg179Cys variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In silico analyses support a deleterious effect of the p.Arg179Cys variant on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.535C>T (p.Arg179Cys) variant is classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 08, 2024 | - - |
Familial aortopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 20, 2018 | Variant summary: ACTA2 c.535C>T (p.Arg179Cys) results in a non-conservative amino acid change in the encoded protein sequence indicated to be located near a key protein-protein interaction site (Moreno_2016). Five of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally asssessed. The variant was absent in 121348 control chromosomes (ExAC). Multiple publications have cited the variant in affected individuals presenting with a multisystemic smooth muscle dysfunction syndrome (MSMDS) and aortic event. Multiple studies indicate the variant was a de novo occurrence (Meuwissen_2012 and Moreno_2016). In addition, other variants affecting the same codon, Arg179His and Arg179Lys, have been reported in affected individuals indicating a potential mutational hot spot. One clinical diagnostic laboratory has submitted a clinical-significance assessments of "likely pathogenic" for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 05, 2019 | Identified in individuals with aortic aneurysms and multisystemic smooth muscle dysfunction syndrome referred for genetic testing at GeneDx in the published literature (Meuwissen et al., 2013; de Grazia et al., 2016; Leong et al., 2016; Moreno et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic (ClinVar Variant ID# 265026; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30300893, 27481187, 23613326, 27567161, 25759435, 27244053, 29300374, 24621862, 29875232, 33199432) - |
Aortic aneurysm, familial thoracic 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 05, 2022 | This variant disrupts the p.Arg179 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20734336, 22752479, 22946110, 24293535, 24621862, 24998021, 26034244). 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 expected to disrupt ACTA2 protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265026). This missense change has been observed in individual(s) with multisystemic smooth muscle dysfunction syndrome and childhood cardiovascular, autonomic and brain anomalies and aortic dissection or aneurysm (PMID: 23613326, 25759435, 27481187, 27567161). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 179 of the ACTA2 protein (p.Arg179Cys). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at L180 (P = 0.0093);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at